Podcasts about PFS

Newcore Gold CEO Luke Alexander shares insights from the Indaba Mining Conference, highlighting the positive sentiment in the market. Luke also provides some context into the commissioning of a pre-feasibility study (PFS) for the Enchi Gold project. The discussion covers the transition from a heap leach to a CIL process flowsheet, the long-term strategy for the Enchi project, and the timeline for the PFS completion.

Feb 16, 2026 – Looking for ways to boost heart health, improve recovery, and enhance longevity? Financial Sense Newshour's Jim Puplava hosts Vic Riffel from Sunlighten to uncover the science and benefits behind infrared saunas. Vic explains how...

Feb 13, 2026 – The job market is being transformed at breakneck speed by artificial intelligence, but not without challenges and opportunities. Today, on Financial Sense Newshour's Big Picture podcast we explain how millions of tech and...

Feb 13, 2026 – Financial Sense Newshour's Jim Puplava interviews energy expert Robert Rapier about the rising demand and controversy surrounding AI, including the proliferation of data centers and their impact on the U.S. power grid...

Feb 13, 2026 – After a dramatic surge to a record 50,000 on the Dow, investors are suddenly rethinking where the market goes next. Is the era of technology-led growth over, or is the new leadership just beginning to unfold in unexpected...

Guest Full Name: Dr. R. Stacy Lindborg, PhDGuest Title: President, Chief Executive Officer, and Board DirectorCompany: IMUNONTicker: IMNNWebsite: https://imunon.com/Guest Bio:Stacy R. Lindborg, PhD, was appointed President and Chief Executive Officer of IMUNON in May 2024. Dr. Lindborg has served on IMUNON's Board of Directors since June 2021. She has nearly 30 years of experience in the pharmaceutical and biotech industries, with a particular focus on R&D, regulatory affairs, executive management, and strategy development. She has designed, hired, and led global teams, guiding long-term visions for growth through analytics and stimulating innovative development platforms to increase productivity.Prior to joining IMUNON, Dr. Lindborg was Executive Vice President and Co-Chief Executive Officer at BrainStorm Cell Therapeutics, where she remains a member of the company's Board of Directors. At BrainStorm, she was accountable for creating and executing clinical development strategies through registration and launch and progressed its novel cell therapy for ALS through a positive Phase 3 Special Protocol Assessment (SPA) study with the U.S. Food and Drug Administration. She frequently interacted with investors and analysts, represented the company in the scientific community and with the media, and played an active role in discussions with potential business partners.Dr. Lindborg previously was Vice President and Head of Global Analytics and Data Sciences, responsible for R&D and marketed products at Biogen. She began her biopharmaceutical career at Eli Lilly and Company, where, over the course of 16 years, she assumed positions of increasing responsibility, including Head of R&D strategy.Dr. Lindborg received an MA and PhD in statistics, and a BA in psychology and math from Baylor University. She has authored more than 200 presentations and 90 manuscripts that have been published in peer-reviewed journals, including 20 first-authored. She has held numerous positions within the International Biometric Society and American Statistical Association and was elected Fellow in 2008.Company Bio:IMUNON is a clinical-stage biotechnology company focused on advancing a portfolio of innovative treatments that harness the body's natural mechanisms to generate safe, effective, and durable responses across a broad array of diseases. IMUNON is developing its non-viral DNA technology across its modalities. The first modality, TheraPlas®, is developed for the gene-based delivery of cytokines and other therapeutic proteins in the treatment of solid tumors where an immunological approach is deemed promising. The second modality, PlaCCine®, is developed for the gene delivery of viral antigens that can elicit a strong immunological response.IMUNON's lead clinical program, IMNN-001, is a DNA-based immunotherapy for the localized treatment of advanced ovarian cancer. IMNN-001 is the first therapy to achieve a clinically effective response in advanced (stage IIIC/IV) ovarian cancer including benefits in both progression-free survival (PFS) and overall survival (OS) in a first-line treatment setting when used with standard of care chemotherapy. IMUNON has completed multiple clinical trials evaluating the potential of IMNN-001, including one Phase 2 clinical trial (OVATION 2), and is currently conducting a Phase 3 clinical trial (OVATION 3). The first patient was dosed in the Phase 3 study in the third quarter of 2025. IMNN-001 works by instructing the body to produce safe and durable levels of powerful cancer-fighting molecules, such as IL-12 and interferon gamma, at the tumor site. Additionally, the Company has completed dosing in a first-in-human study of its COVID-19 booster vaccine (IMNN-101).

Feb 12, 2026 – FS Insider interviews Dr. Alan D. Thompson, creator of The Memo, one of the world's leading AI newsletters, as he discusses the newly announced Genesis Mission—the U.S. government's largest-ever AI data initiative, rivaling...

Host Dr. Davide Soldato and guests Dr. David Einstein and Dr. Ravi Madan discuss JCO article, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations," underscoring the need for a consensus on clinical trial designs implementing novel endpoints in this population, the importance of PSA doubling time as a prognostic factor and with an emphasis on treatment de-escalation to limit toxicity and improve patient outcomes. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO authors Dr. David Einstein and Dr. Ravi Madan. Dr. Einstein is a medical oncologist specializing in genitourinary malignancy working at Beth Israel Deaconess Medical Center, part of the DFCI Cancer Center, and an assistant professor at Harvard Medical School. Dr. Madan is a senior clinician at the National Cancer Institute (NCI), where he focuses on conducting clinical research in prostate cancer, particularly in the field of immunotherapy. Today, we will be discussing the article titled, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations." So, thank you for speaking with us, Dr. Einstein and Dr. Madan. David Einstein: Thanks for having us. This is a great pleasure. Ravi Madan: Appreciate being here. Davide Soldato: So, I just want to start from a very wide angle. And the main question is why did you feel that there was the need to convey a consensus and a working group to talk about this specific topic: biochemically recurrent prostate cancer? What has been the change in current clinical practice and in the trial design that we are seeing nowadays? And so, why was it necessary to convey such a consensus and provide considerations on novel clinical trials? David Einstein: Yeah, so I think it's very interesting, this disease state of biochemically recurrent prostate cancer. It's very different from other disease states in prostate cancer, and we felt that there was a real need to define those differences in clinical trials. Years ago, metastatic castration-resistant prostate cancer was the primary disease state that was explored, and over time, a lot of things shifted earlier to metastatic disease defined on a CAT scan and bone scan to an earlier disease state of metastatic castration-sensitive prostate cancer. And the clinical trial principles from late-stage could be applied to MCSPC as well. However, BCR is very different because the patients are very different. And for those reasons, there are unique considerations, especially in terms of toxicity and treatment intensity, that should be applied to biochemically recurrent prostate cancer as opposed to just using the principles that are used in other disease states. And for that reason, we thought it was very important to delineate some of these considerations in this paper with a group of experts. Davide Soldato: Thanks so much. So, one of the main changes that have been applied in recent years in clinical practice when looking at biochemically recurrent prostate cancer is the use of molecular imaging and particularly of PSMA PET. So, first of all, just a quick question: was the topic of the consensus related on which threshold of PSA to use to order a PET scan to evaluate this kind of patient? David Einstein: Yeah, thanks for that question. It's a super important one. The brief answer is that no, we did not address questions about exactly when clinicians would decide to order scans. We were more concerned with the results of those scans in how you define different disease states. But I think as a broader question, I think a lot of folks feel that finding things on a scan equates that with what we used to find on conventional scans. And fundamentally, we actually sought to redefine that disease space as something that's not equivalent to metastatic disease, and rather coined the term "PSMA-positive BCR" to indicate that traditional BCR prognostic criteria and factors still apply, and that these patients have a distinct natural history from those with more advanced metastatic disease. Ravi Madan: And if I may just add that the National Cancer Institute is running a trial where we're prospectively monitoring PSMA-positive BCR patients. And that data is clearly showing that, much like what we knew about BCR a decade ago, PSMA findings in BCR patients do not change the fact that overall, BCR is an indolent disease state. And the findings, which are usually comprised of five- to seven-millimeter lymph nodes, do not endanger patients or require immediate therapy. And so, while PSMA is a tool that we can be using in this disease state, it doesn't really change the principal approach to how we should manage these patients. And as Dr. Einstein alluded to, there is a drive to create a false equivalency between PSMA-positive BCR and metastatic castration-sensitive prostate cancer, but that is not supported by the data we're accumulating or any of the clinical data as it exists. Davide Soldato: One thing that it's very important and you mentioned in your answer to my question was actually the role of PET scan and conventional imaging, so CAT scan and bone scan that we have used for years to stage patients with metastatic prostate cancer. And you mentioned that there is a distinction among patients who have a positive PET scan and a BCR, and patients who have a positive conventional imaging. And yet, we know that sometimes the findings of the PET scan are not always so clear to interpret. So, I just wanted to understand if the consensus reached an agreement as to when to use conventional imaging to potentially resolve some findings that we have on PET scan among thess patients with BCR? David Einstein: Yeah, I think there's a number of questions actually buried within that question. One of which is: does PSMA PET result in false positives? And the answer has definitely been yes. There's a known issue with false-positive rib lesions. And so, first and foremost, we need to be very careful in calling what truly is suspicious disease and what might actually not be cancer or might be something that is totally separate. So I think that's the first part of the answer to that question. The second is to what extent do we need to use paired PET and conventional imaging to define this disease state? In other words, do you have to have positive findings on one and negative findings on the other in order to enter this definition? The challenge there, as we discussed, is that logistically, oftentimes it's hard to get patients to do multiple sets of scans to actually create that definition. Sometimes it's difficult to get insurers to pay for such scans. And finally, it's hard to sometimes blind radiologists to the results of one scan in reading the other. So, we did have some deliberations about to what extent you could use some of the CAT scan portion of a PSMA PET in order to at least partially define that. We also talked about using bone scans to confirm any bone findings seen on PET. But I think another important part of this is not just the baseline imaging, but also what's going to be done serially on a study in order to define responses and progression. And that's sort of a whole separate conversation about to what extent you can interpret changes in serial PET. Ravi Madan: And just to pick up on the key factor here, I think that the PSMA PET in BCR is pretty good at defining lymph node disease, and that's actually predominantly 80 to 90 percent of the disease seen on these findings. It might be pretty good at also defining other soft tissue findings. The real issues come to bone findings. And one thing the group did not feel was appropriate was to just define only PSMA-positive bone findings confirmed on a CT bone window. There's not really great data on that, but the working group felt that, when in the rare situation, because it is relatively rare, a PSMA-positive finding is in a bone, a bone scan should be done. And it's worth noting that Phu Tran, who is a co-author and a co-leader of this working group, his group has already defined that underlying genomics of conventionally based lesions, such as bone scan, are more aggressive than findings on next-gen imaging, such as PSMA. So, there is also a genomic underlying rationale for defining the difference between what is seen on a PET scan in a bone and what is seen on a bone scan. Davide Soldato: Coming back to this issue of PET PSMA sometimes identifying very small lesions where we don't see any kind of correlates on conventional imaging or where we see only very little alteration on the bone scan or in the CT scan, was there any role that was imagined, for example, for MRI to distinguish this type of findings on the PET scan? Ravi Madan: So, I think that, again, what can be identified on a PSMA frequently cannot be seen on conventional imaging. We didn't feel that it was a requirement to get an MRI or a CT to necessarily confirm the PSMA findings. I think that generally, we have to realize that in this disease state, that questionable lesions are going to be seen on any imaging, including PSMA. We've actually probably put way too much faith in PSMA findings thus far, as Dr. Einstein alluded to with some of the false positives we're seeing. So, I think that these false positives are going to have to be baked into trials. And in terms of clinical practice, it highlights the need to again, not overreact to everything we see and not necessarily need to biopsy everything and put patients' health in jeopardy to delineate a disease that's indolent anyway. Davide Soldato: Thanks so much. That was very clear. So, basically, the main driver was really also the data showing that if we have a BCR, so a patient with a biochemically recurrent disease that is positive on the conventional imaging, this is usually associated with a different aggressiveness of the disease. But coming back to a comment that you made before, Dr. Madan, you said that even if we talk about PSMA-positive BCR, we are still talking about BCR and the same criteria should apply. So, what we have used for years in this space to actually try to stratify the prognosis of patients is the PSA doubling time, so how quickly the PSA rises over time. So, coming back to that comment, was the consensus on the PSA doubling time basically retained as what we were using before, so defining patients with a doubling time less than 12 months, 10 months, 9 months, as patients with a higher risk of progressing in terms of developing metastatic disease? Ravi Madan: Yes, so that's a very important point. And the working group defined high-risk BCR as a PSA doubling time less than six months. And this really comes from Johns Hopkins historical data, which shows that if your doubling time is three months or less, there's about a 67 percent chance of metastasis at five years. If it's between three and six months, it's 50 percent. And if it's over six months, if it's between six and nine months, it's roughly only 27 percent. There are trials that are accruing with eligibility criteria that they may describe as high-risk that are beyond six months, but the data as really it's been defined in the literature highlights that truly high-risk BCR is less than six months. And the working group had a consensus on that opinion, and that was our recommendation. David Einstein: And I think an important follow-on to that is that's regardless of PET findings, right? And so, we present a couple of case studies of patients with positive PET findings who have a long doubling time, in whom the disease is in fact indolent, as you would have expected from a traditional BCR prognostic standpoint. Obviously, there are patients in whom they have fast doubling times, and even if they do not have PET findings, that doesn't make them not high-risk. Ravi Madan: And just to follow up that point, I will let you know a little bit of a free preview that my colleague Melissa Abel from the NCI will be presenting PSMA findings in the context of PSA doubling time at ASCO GU if that data is accepted. Davide Soldato: Looking forward for those data because I think that they're going to clarify a lot of the findings that we have in this specific population. And coming back to one of the points that we made before, so PET PSMA has a very high ability to discriminate also a very low burden of disease, which we currently refer to as oligometastatic biochemically recurrent prostate cancer, which is not entirely defined as an entity. But what we are seeing both in some clinical trials, which use mainly conventional imaging, but also what we're starting to see in clinical practice, is that frequently we use the metastasis-directed therapy to treat these patients. So, just a little bit of a comment on the use of this type of strategy in clinical practice and if the panel thought of including this as, for example, a stratification criteria or mandated in the design of novel clinical trials in the field of BCR? David Einstein: Yeah, I think that's an incredibly important point. You know, fundamentally, there's a lot of heterogeneity in practice where some folks are using local salvage approaches, some are using systemic therapies, in some cases surveillance may be reasonable, or some combination of these different strategies. We certainly have phase two data from multiple trials suggesting that met-directed therapy may help buy patients time off of treatment until subsequent treatments are started. And that in and of itself may be an important goal that we can come back to in discussing novel endpoints. I think what our panel acknowledged was that, in some sense, the clinical practice has gotten even farther ahead than where the data are, and this is being offered pretty routinely to patients in practice. And so, what became clear was that we, in developing clinical trials, cannot forbid investigators from doing something that would be within their usual standard of care, even if it might not be supported by the most robust data. But at minimum, it definitely should be used as a stratification factor, or in some trial designs, you can do met-directed therapy after a primary endpoint is assessed. And that offers a compromise between testing, say, the effect of a systemic therapy but also not excluding patients and investigators from doing what they would have done had they not been on a study. Ravi Madan: And I would just like to follow up your phrasing in the question of "oligometastatic prostate cancer." We have a figure in the paper and it highlights the fact that, unfortunately, that term in prostate cancer is imaging agnostic. And we've already discussed in this podcast, as well as in the paper, that imaging used to define a metastatic lesion, whether it's PSMA or conventional imaging, carries with it a different clinical weight and a different prognosis. So, we feel in the working group, that the correct term for this disease state of PSMA-positive BCR is just that: PSMA-positive BCR. We also have to realize that when we talk about oligometastatic disease, while it's imaging agnostic, it seems to be numerically based, whether it's five or three or 10 depending on the trial. But PSMA-positive BCR does not have a limit in terms of the number of lesions. And so again, we just feel that there is an important need to delineate what we're seeing in this disease state, which again is PSMA-positive BCR, and that should be differentiated frankly from oligometastatic disease defined on other imaging platforms. David Einstein: Right, and that also makes clear that patients can have polyfocal disease on PET that still is not what we would consider metastatic, but goes beyond the traditional definition of oligometastatic. So, in other words, just because someone has PET-detected disease only, that does not automatically equate with oligometastatic. Davide Soldato: Thanks so much. So, you were speaking a little bit, Dr. Einstein, about the different types of treatment that we can propose or not propose to this patient because you mentioned, for example, that in clinical practice MDT, so metastasis-directed therapy, is becoming more and more used. For these patients, we can potentially use systemic treatments, which include androgen deprivation therapy, which can be given continuously or in an intermittent fashion. And recently, we can also use novel systemic therapies, for example, enzalutamide, to treat this type of patient. So, given that the point of the consensus was really to provide consideration for novel clinical trials in this space, what was the opinion on the panel regarding the control arm? So, if we're looking at a novel therapy in the BCR space, does the control arm need to include a therapy or not? And if so, which therapy? David Einstein: Yeah, this is a super important question and one that's subject to a lot of discussion, especially in light of recent data from EMBARK. What we came to a consensus around was the fact that neither MDT nor systemic therapy should be required as a control arm on BCR trials. And we can talk about a number of reasons for that. There's also the pragmatics of what investigators might actually accrue patients to and what they would consider their standard of care, and that's important to factor in, too. I think that one of the major goals of our working group was outlining what kinds of trials we would like to see in the future and where the limitations of the current data stand. For example, EMBARK proposes a strategy of a single treatment discontinuation and resumption at a predefined threshold indefinitely. That's probably not how most people are practicing. Most folks are probably using some version of intermittent therapy as they would have before this trial, but we actually don't have any data supporting that. Moreover, we don't have data comparing different intermittent strategies to one another. We don't know what the right thresholds are, we don't know how much time we buy patients off treatment, and we don't know to what extent MDT modifies that. And so, those are all really important questions to be asking in future versions of these trials. I'd say my second point would be that a lot of drug development is happening with novel therapies that are not hormonal, trying to bring them into this space. And when you think about trying to compare one of those types of therapies to a hormonal therapy on short-term endpoints, the hormonal therapy is always going to win. Hormonal therapy is almost universally effective, it will bring down PSAs, and it will prolong, quote-unquote, "progression." The downside of that is that hormonal therapy doesn't actually modify the disease, it suppresses it, and it tends to have fairly transient effects once you remove it. And so, part of our goal was in trying to figure out some novel endpoints that would allow these novel types of therapies to be examined head-to-head against a more traditional type of hormonal therapy and have some measurement of some of the more long-term impacts. Davide Soldato: So, jumping right into the endpoints, because this is a very relevant and I think very well-constructed part of the paper that you published. Because in the past we have used some of these endpoints, for example, metastasis-free survival, as potentially a proxy for long-term outcomes. But is this the right endpoint to be using right now, especially considering that frequently this outcome is measured using conventional imaging, but we are including in these trials patients who are actually negative on conventional imaging but have a positive PSMA when they enter this type of trial? David Einstein: Yeah, there's a number of challenges with those types of endpoints. One of which is, as you say, we're changing the goalposts a little bit on how we're calling progression. We still don't exactly understand what progression on PET means, and so that's something that is challenging. That said, we're also cognizant of the fact that many times investigators are likely to get PET scans in the setting of rising PSA, and that's going to affect any endpoint that relies purely on conventional imaging. So, there's some tension there between these two different sets of goalposts. One thing that we emphasize is that not only are there some challenges in defining those, but also there're challenges in what matters to a patient. So, if a progression event occurs in the form of a single lesion on a PET scan or even a conventional image, that might be relevant for a clinical trial but might be less relevant for a patient. In other words, that's something that, in the real world, an investigator might use serial rounds of metastasis-directed therapy or intermittent therapy to treat in a way that doesn't have any clinical consequences for the patient necessarily. In other words, they're asymptomatic, it's not the equivalent of a metastatic castration-resistant disease progressing. And so, we also need to be cognizant of the fact that if we choose a single endpoint like PFS, that there's going to be many different versions of progression, some of which probably matter clinically more than others, and some of which are more salvageable by local therapies than others. Ravi Madan: So I think the working group really thoughtfully looked at the different options and underscored perhaps strengths and weaknesses, and I think that's presented as you mentioned in the paper. But I think it's also going to depend on the modality, the approach of the therapeutic intervention. In some cases if it's hormone-based, then maybe PSA is providing some early metrics, maybe metastasis-free survival is more relevant in a continuous therapy, but intermittent therapies might have a different approach. There's emerging immunotherapy strategies, radiopharmaceutical strategies, they might have some more novel strategies as well. I think we have to be open-minded here, but we also have to be very clear: we do not know what progression is on a PSMA scan. Just new lesions may not carry the clinical significance that we think, and we may not know what threshold that ultimately becomes clinically relevant is. So, I do think that there was some caution issued by the working group about using PSMA as an endpoint because we still do not have the data to understand what that modality is telling us. Again, I'm optimistic that the National Cancer Institute's prospective data set that we've been collecting, which has over 130 patients now, will provide some insights in the months and years ahead. Davide Soldato: So, just to ask the question very abruptly, what would you feel like the best endpoint for this type of trials is? I understand that is a little bit related to the type of treatments that we're going to use, whether it's intermittent, whether it's continuous, but do we have something that can encapsulate all of the discussion that we have up until this point? David Einstein: Yeah, so that's a perfect segue to the idea of novel endpoints, which we feel are very important to develop in these novel disease spaces. So, one thing that we discussed was an endpoint called treatment-free survival, which conceptually you can think of as exactly what it sounds like, but statistically you actually have to do some work to get there. And so essentially, you imagine a series of Kaplan-Meier curves overlaid: one about overall survival, one time to next therapy, one time on initial therapy. You can actually then take the area under those curves or between those curves and essentially sum it up using restricted mean survival time analysis. And that can give you a guide about the longitudinal experience of a patient: time spent on treatment versus off treatment; time spent with toxicity versus without toxicity. And importantly, each one of those time-to-event metrics can be adjusted depending on exactly what the protocol is and what is allowed or not allowed and what's prespecified as far as initiation of subsequent therapies. So, we felt that this was a really important endpoint to develop in this disease space because it can really capture that longitudinal aspect. It can really reward treatments that are effective in getting durable responses and getting patients off of therapy, because unfortunately, PFS-based endpoints generally reward more or longer systemic therapy versus shorter or no systemic therapy, and that's sort of an artificial bias in the way those endpoints are constructed. So, I think that there are challenges of course in implementing any new endpoint, and some of the things that are really critical are collecting data about toxicity and about subsequent therapies beyond what a typical trial might collect. But I think in this kind of disease space, that longitudinal aspect is critical because these are really patients who are going to be going through multiple rounds of therapy, going to be going on and off treatments, they're going to be using combinations of local and systemic therapies. And so, any one single endpoint is going to be limited, but I think that really highlights the limitations of using PFS-based endpoints in this space. Ravi Madan: I also think that in the concept of treatment-free survival lies one of the more powerful and, honestly, I was surprised by this, that it was so universally accepted, recommendations from the committee. And that was that the general approach to trials in this space should be a de-escalation of the EMBARK strategy as it's laid out with relatively continuous therapy with one pause. And so, I think again, buried in all of this highlights the need for novel endpoints like treatment-free survival. We get to the fact that these are patients who are not at near-term clinical risk from symptoms of their disease, so de-escalating therapies does not put them at risk. And if you look at, for example, lower-volume metastatic castration-sensitive prostate cancer, it's become realized that we need to de-escalate, and there are now trials being done to look at that. Historically, we know that BCR is an indolent disease process for the vast majority of patients who are not at near-term risk from clinical deterioration. So, therefore, we shouldn't wait a decade into abundant BCR trials to de-escalate. The de-escalation strategy should be from the outset. And that was something the committee really actually universally agreed on. David Einstein: And that de-escalation can really take multiple forms. That could be different strategies for intermittent therapy, different start-stop strategies. It could also mean actually intensifying in the short-term with the goal long-term de-intensification, kind of analogous to kidney cancer where we might use dual checkpoint inhibitors up front with some higher upfront toxicity but with the hope of actually long-term benefit and actually being able to come off treatment and stay in remission. Those kinds of trade-offs are the types of things that are challenging to talk about. There's not a one-size-fits-all answer for every patient. And so, that's why some of these endpoints like treatment-free survival would be really helpful in actually quantifying those trade-offs and allowing each patient to make decisions that are concordant with their own wishes. Davide Soldato: Thanks so much. That was very clear, especially on the part of de-escalation, because, as you were mentioning, I think that we are globally talking about a situation, a clinical situation, where the prognosis can be very good and patients can stay off treatment for a very long period of time without compromising long-term outcomes. And I think that well-constructed de-escalation trials, as you were mentioning and as the consensus endorsed, are really needed in this space also to limit toxicity. This brings us to the end of this episode. So, I would like to thank again Dr. Einstein and Dr. Madan for joining us today. David Einstein: We really appreciate the time and the thought, and I think that even starting these types of discussions is critical. Even just recognizing that this is a unique space is the beginning of the conversation. Ravi Madan: Yeah, and I want to thank JCO for giving us this forum and the opportunity to publish these results and all the expert prostate cancer investigators who were part of this committee. We produced some good thoughts for the future. Davide Soldato: We appreciate you sharing more on your JCO article titled, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations." If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinion of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Aftermath Silver CEO Ralph Rushton joined Steve Darling from Proactive to announce the commencement of a Pre-Feasibility Study (PFS) for the company's Berenguela silver-copper-manganese project in southern Peru, marking a significant milestone as the company advances the asset toward a potential production decision. Rushton told Proactive that the move to initiate a PFS follows the successful completion of a C$20 million equity financing and an extensive 82-hole infill drilling program carried out in 2025. The drill campaign intersected mineralization in 95% of the holes, substantially increasing geological confidence across the project. The resulting updated Mineral Resource Estimate materially strengthened the company's understanding of the deposit, confirming robust silver and copper mineralization across key zones and supporting the decision to progress Berenguela to the next stage of development. The PFS will build on this improved geological model and is expected to outline updated project economics, mine planning parameters, and development scenarios. Berenguela currently hosts Measured and Indicated Resources of approximately 122.5 million ounces of silver and 717.1 million pounds of copper, positioning it as a significant polymetallic development asset in the region. While advancing the PFS, Aftermath Silver plans to maintain exploration momentum across its portfolio. The company will continue drilling key exploration targets at Berenguela, as well as at its Challacollo silver project in Chile, as it seeks to expand resources and unlock additional value. Rushton emphasized that the initiation of the PFS represents a pivotal step in transforming Berenguela from an advanced exploration asset into a potential future mining operation, while ongoing exploration efforts aim to further enhance the company's growth pipeline. #proactiveinvestors #aftermathsilverltd #tsxv #aag #otcqx #aagff #mining #BerenguelaProject #SilverProject #CopperProject #Manganese #PreFeasibilityStudy #PFS #MiningDevelopment #PeruMining #Polymetallic #ResourceEstimate #SilverMining #CopperMining #MiningExploration #MineralResources #Challacollo #ChileMining #MiningGrowth #ProductionPath #NaturalResources

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Feb 6, 2026 – What just happened to silver? After a historic crash wiped out billions, is the bull market already over? In this critical interview, Jim Puplava sits down with The Morgan Report's Dave Morgan to dissect the violent sell-off and its stunning aftermath....

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In this episode of the Oncology Brothers podcast, we dived deep into the recent FDA approval of T-DXd (trastuzumab deruxtecan) plus Pertuzumab for the treatment of HER2-positive metastatic breast cancer. Joined by Dr. Sara Tolaney, the lead author of the DESTINY-Breast 09 study, where we discussed the findings that show a significant improvement in progression-free survival (PFS) from 26.9 months to 40.7 months, with a hazard ratio of 0.56. Key topics included: • The design and findings of the DESTINY-Breast09 trial • Comparison with traditional treatment regimen THP (trastuzumab, pertuzumab, and taxane) • The implications of these findings for clinical practice • The role of maintenance therapy and the potential for personalized treatment strategies • Common side effects associated with T-DXd and pertuzumab, including ILD (Interstitial Lung Disease) Join us as we explore the future of HER2-positive breast cancer treatment and the exciting developments that are changing the landscape for patients. Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/  Don't forget to subscribe for more insights on treatment algorithms, FDA approvals, and conference highlights! #HER2positiveBreastCancer, #TrastuzumabDeruxtecan, #DestinyBreast09, #MetastaticBreastCancer, #OncologyBrothers

Feb 3, 2026 – When markets soar but Main Street struggles, what signals should you trust? In this episode, Peter Boockvar, author of The Boock Report, explores the implications of Trump's choice for new Fed Chair, the recent parabolic move...

Feb 2, 2026 – On today's edition of the Lifetime Planning segment on the Financial Sense Newshour, Jim Puplava welcomes Jennifer Stevens from International Living to talk about their newly released Best Places to Retire in 2026...

Dr. Sonam Puri discusses the full update to the living guideline on stage IV NSCLC with driver alterations. She shares a new overarching recommendation on biomarking testing and explains the new recommendations and the supporting evidence for first-line and subsequent therapies for patients with stage IV NSCLC and driver alterations including EGFR, MET, ROS1, and HER2. Dr. Puri talks about the importance of this guideline and rapidly evolving areas of research that will impact future updates. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02822    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Sonam Puri from Moffitt Cancer Center, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2026.3.0." It's great to have you here today, Dr. Puri. Dr. Sonam Puri: Thanks, Brittany. Brittany Harvey: And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Puri, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content that we're here today to talk about, Dr. Puri, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is updated on an ongoing basis. So, what data prompted this latest update to the recommendations? Dr. Sonam Puri: So Brittany, non-small cell lung cancer is one of the fastest-moving areas in oncology right now, particularly when it comes to targeted therapy for driver alterations. New data are emerging continuously from clinical trials, regulatory approvals, real-world experience, which is exactly why these are living guidelines. The goal is to rapidly integrate important advances as they happen, rather than waiting for years for a traditional update. Since the last full update of the ASCO Stage IV Non-small Cell Lung Cancer Guideline with Driver Alterations published in 2024, there have been seven new regulatory approvals and changes in first-line therapy for some driver alterations. [This version] of the "Stage IV Non-small Cell Lung Cancer Guidelines with Driver Alterations" represents a full update, which means that the panel reviewed and refreshed every applicable section of the guideline to reflect the most current evidence across therapies including sequencing and clinical decision-making. This is to ensure that clinicians have up-to-date practical guidelines that keep pace with how quickly the field is evolving. Brittany Harvey: Absolutely. As you mentioned, this is a very fast-moving space and this full update helps condense all of those versions that the panel reviewed before into one document, along with additional approvals and new trials that you reviewed during this time period. So then, the first aspect of the guideline is there's a new overarching recommendation on biomarker testing. Could you speak a little bit to that updated recommendation? Dr. Sonam Puri: Yeah, definitely. So the panel has discussed and provided recommendations on comprehensive biomarker testing and its importance in all patients diagnosed with non-small cell lung cancer. Ideally, biomarker testing should include a broad-based next-generation sequencing panel, rather than single-gene tests, along with immunohistochemistry for important markers such as PD-L1, HER2, and MET. These results really drive treatment decisions, both in frontline settings for all patients diagnosed with non-small cell lung cancer and in subsequent line settings for patients with non-small cell lung cancer harboring certain targetable alterations. Specifically in the frontline setting, it helps determine whether a patient should receive upfront targeted therapy or immunotherapy-based approach. We now have strong data that shows that complete molecular profiling results before starting first-line therapy is associated with better overall survival and actually more cost-effective care. Using both tissue and blood-based testing can improve likelihood of getting actionable results in a timely way, and we've also provided guidance on platforms that include RNA sequencing, which are specifically helpful for identifying gene fusions that might be otherwise missed with other platforms. On the flip side, outside of a truly resource-limited setting, single-gene PCR testing really should not be routine anymore. This is what the panel recommends. It's less sensitive and inefficient and increases the risk of missing important actionable alterations. Brittany Harvey: Understood. I appreciate you reviewing that recommendation. It really helps identify critical individual factors to match the best treatment option to each individual patient. So then, following that recommendation, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer with a driver alteration? Dr. Sonam Puri: Since the last full update in 2024, there have been four additional interim updates which were published across 2024 and 2025. Compared to the last version, there have been several updates which have been included in this full update. One of the most important shifts has been in first-line treatment of patients with non-small cell lung cancer harboring the classical, or what we call as typical, EGFR mutation. The current version of the recommendation is based on the updated survival data from the phase III FLAURA2 and MARIPOSA studies, based on which the panel recommended to offer either osimertinib combined with platinum-pemetrexed chemotherapy or the combination of amivantamab plus lazertinib in the first-line treatment of classical EGFR mutations. And these recommendations, as I mentioned, are grounded in the results of the FLAURA2 and MARIPOSA trials, both of which demonstrated improvement in progression-free survival and overall survival compared to osimertinib alone in patients with common EGFR mutations. That being said, the panel actually spent significant time discussing the toxicities associated with these treatments as well. These combination approaches come with higher toxicity, longer infusion time, increased treatment frequency. So while combination therapy is now recommended as preferred, the panel has recommended that osimertinib monotherapy remains a reasonable option, particularly for patients with poor performance status and for those who are not interested in treatment intensification after knowing the risks and benefits. Brittany Harvey: Absolutely. It's important to consider both those benefits and risks of those adverse events that you mentioned to match appropriately individualized patient care. So then, beyond those recommendations for first-line therapy, what is new for second-line and subsequent therapies? Dr. Sonam Puri: So this is a section that saw several major updates, particularly again in the EGFR space. The first was an update on treatment after progression on osimertinib for patients with classical EGFR mutation. Here the panel recommends the combination of amivantamab plus chemotherapy, and this recommendation was based on the phase III MARIPOSA-2 trial, which compared amivantamab plus chemotherapy with chemotherapy alone with progression-free survival as the primary endpoint. The study met its primary endpoint, showing an improvement in median PFS with the combination of amivantamab plus chemotherapy compared to chemotherapy alone. And as expected, the combination was associated with higher toxicity. So, although the panel recommends this regimen, the panel emphasizes that patients should be counseled on the side effects which may be moderate to severe with the combination therapy approach. In addition, a new recommendation was added for patients who are not candidates for amivantamab plus chemotherapy. In those cases, platinum-based chemotherapy with or without continuation of osimertinib may be offered, and the option of continuing osimertinib with chemotherapy was recommended and supported by data from a recently presented phase III COMPEL study, which randomized 98 patients with EGFR exon 19 deletion or L858R-mutated advanced non-small cell lung cancer who had experienced no CNS progression on first-line osimertinib, and these patients were randomized to receive platinum-pemetrexed chemotherapy with osimertinib or placebo. Although this study was small, it demonstrated a PFS benefit with continuation of osimertinib with chemotherapy, and this approach may be appropriate for patients without CNS progression who prefer or require alternatives to more intensive treatment strategies. Next was an update on options for patients with EGFR-mutated lung cancer after progression on osimertinib and platinum-based chemotherapy. Here the panel recommended that for patients whose disease has progressed after both osimertinib and platinum-based chemotherapy, a new drug known as datopotamab deruxtecan can be offered as a treatment option. And this treatment recommendation was based on evaluation of pooled data from the TROPION-Lung01 and TROPION-Lung05 study, in which in the pooled analysis about 114 patients with EGFR-mutant non-small cell lung cancer were treated with Dato-DXd, 57% of whom had received three or more prior lines of treatment, and what was observed was an overall response rate of 45% with a median duration of response of 6.5 months. So definitely promising results. Next, we focused on updates to subsequent therapy options for patients with another type of EGFR mutation known as EGFR exon 20 insertion mutations. In this section, the panel added sunvozertinib as a subsequent line option after progression on platinum-based chemotherapy with or without amivantamab. Sunvozertinib is an oral, irreversible, and selective EGFR tyrosine kinase inhibitor with efficacy demonstrated in the phase II WU-KONG6 study conducted in Chinese patient population. In this study, amongst 104 patients with platinum-pretreated EGFR exon 20 mutated non-small cell lung cancer, the observed response rate was 61%. Staying in the EGFR space, the panel added a recommendation for patients with acquired MET amplification following progression on EGFR TKI therapy. In these situations, the panel recommended that treatment may be offered with osimertinib in combination with either tepotinib or savolitinib. As our listeners may know, MET amplification occurs in approximately 10% to 15% of patients with EGFR-mutated non-small cell lung cancer when they progress on third-generation EGFR TKIs, and detection of MET amplification is done with various methods, such as tissue-based methods like FISH, NGS, and IHC, as well as ctDNA-based NGS with variable cut-offs. Over the last few years, several studies have informed this recommendation. I'm going to be discussing some of them. In the phase II ORCHARD trial, 32 patients with MET-amplified non-small cell lung cancer after progression on first-line osimertinib were evaluated, where the combination of osimertinib plus savolitinib achieved an overall response rate of 47% with a duration of response of 14.5 months. More recently, the phase II SAVANNAH trial reported outcomes in 80 patients with MET-amplified tumors after progression on osimertinib, and in this patient population, the combination of savolitinib and osimertinib achieved an overall response rate of 56% with a median PFS of 7.4 months. And lastly, the phase II single-arm INSIGHT 2 trial assessed the efficacy of osimertinib plus tepotinib in patients with advanced EGFR-mutant non-small cell lung cancer who had disease progression following first-line osimertinib therapy. And in this study, in a cohort of 98 patients with MET-amplified tumors confirmed by central testing, the overall response rate with the combination was 50% with a duration of response of 8.5 months. So definitely informing this guideline recommendation. Next, we had an update on recommendation in patients with ROS1-rearranged non-small cell lung cancer. For patients with ROS1-rearranged non-small cell lung cancer, the panel recommended specifically for patients who progressed after first-line ROS1 TKIs, the addition of taletrectinib as a new option alongside repotrectinib. And this recommendation was based on analysis of the results of the TRUST-I and TRUST-II studies, which showed that amongst 113 tyrosine kinase inhibitor-pretreated patients, taletrectinib achieved a confirmed overall response rate of 55.8% with a median duration of response of 16.6 months and a median PFS of 9.7 months, a very promising agent. Finally, for patients with HER2 exon 20 mutated non-small cell lung cancer, the panel added two new oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib, as options in addition to T-DXd and after exposure to T-DXd. These recommendations are based on early phase data from two trials: the phase I Beamion LUNG-01 study, which evaluated zongertinib, and the phase I/II SOHO-01 study that evaluated sevabertinib. In this study, zongertinib demonstrated an overall response rate of 71% in previously treated patients, with an overall response rate of 48% amongst patients who had received prior HER2-directed ADCs including T-DXd. Sevabertinib in its early phase study showed an overall response rate of 64% in previously treated but HER2 therapy-naive patients, and an overall response rate of 38% in patients previously exposed to HER2-directed therapy. The panel believes that both agents had manageable toxicity profile and represent meaningful new options for this patient population. Brittany Harvey: Certainly, it's an active space of research, and I appreciate you reviewing the evidence underpinning all of these recommendations for our listeners. So, it's great to have these new options for patients in the later-line settings. And given all of these updates in both the first and the later-line settings, what should clinicians know as they implement this latest living guideline update, and how do these changes impact patients with non-small cell lung cancer? Dr. Sonam Puri: Some great questions, Brittany. I think for clinicians when implementing this update, I think about two practical steps. First is reiterating the importance of comprehensive biomarker testing. That is the only way to identify key drivers and resistance mechanisms that we are now targeting. And second, picking a first-line strategy that balances efficacy and toxicity and patient preference for your specific patient. I think informed decision-making, shared decision-making is more important than any time right now. It has always been important, but definitely very important now. For patients, this guideline brings recommendations on more personalized treatment options for both first-line and post-progression settings, which potentially means better outcomes. But it is also very important for our patients to continue to have informed conversations about side effects, time commitment, and what matters most to them with their providers. The panel in this version of the guideline specifically acknowledges the real-world barriers that prevent patients from receiving guideline-concordant therapy, including challenges with access to comprehensive molecular testing and treatment availability, and the panel emphasizes on the importance of shared decision-making, and we provide practical discussion points to help clinicians navigate these conversations with the patient. In addition, the panel has also addressed common real-world clinical complexities, such as treating elderly or frail patients, managing multiple chronic conditions, considerations around pregnancy and fertility, and certain disease scenarios such as oligoprogression or oligometastatic disease. And where available, the guideline summarizes this existing data to support informed individual decision-making in these complex situations. Brittany Harvey: Shared decision-making is really paramount, especially with all of the options and weighing the risks and benefits and considering the individual circumstances of each patient that comes before a clinician. We've talked a lot about all of the new studies that the panel has reviewed, but what other studies or areas of research is the panel examining for future updates to this living guideline as it continues to be updated on an ongoing basis? Dr. Sonam Puri: Yes, definitely, so much to look forward to, right? Looking ahead, the panel is closely monitoring several rapidly evolving areas that are likely to shape future updates of the guideline. This includes emerging data from ongoing later-phase studies, particularly the studies that are evaluating these new targeted agents moving to earlier lines of therapy, alongside studies evaluating additional combination strategies or more refined approaches to treatment sequencing. We're also closely watching advances in biomarker testing, the evolving understanding of resistance mechanisms, development of new targets, and promising therapeutic agents. I think ultimately the living guideline exists to help clinicians and patients navigate this rapidly evolving field, and we would like to ensure that scientific advances are rapidly translated into better, more personalized patient care. Brittany Harvey: Definitely. We'll look forward to those updates from those ongoing trials and future areas of research that you mentioned to provide better options for patients with non-small cell lung cancer and a driver alteration. So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Puri. Dr. Sonam Puri: Thanks so much. Thanks so much for the opportunity. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. There's also a companion episode with Dr. Reuss on the related living guideline on stage IV non-small cell lung cancer without driver alterations that listeners can find in their feeds as well. And if you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Jan 30, 2026 – Has the dollar's reign ended? In this detailed interview, Jim Puplava sits down with veteran metals strategist Greg Weldon to dissect the powerful fundamentals driving metals and the broader commodities prices, from unsustainable...

Jan 30, 2026 – Market optimism faces a reality check as Financial Sense Newshour interviews Craig Johnson, renowned for his accurate market calls. Despite record highs, Johnson discusses recent sell-offs triggered by weaker-than-expected...

Jan 30, 2026 – Amid a global race for resources, Financial Sense's Jim Puplava unpacks the “invisible chokehold” disrupting energy and minerals supply chains in the US and around the world. Puplava outlines America's decline in coal and nuclear power...

Jan 27, 2026 – Our next guest, David Woo, CEO of David Woo Unbound, believes 2026 could be the year the impossible becomes plausible, as we shift into a post rules-based international order. While the US and China battle for dominance...

Jan 26, 2026 – What if you could recharge your body's cellular battery as easily as you charge your phone? In this groundbreaking conversation, Jim Puplava sits down with Biocharger CEO and co-founder Jim Law to explore a revolutionary device...

Jan 26, 2026 – Gold and silver prices have gone parabolic. CPM Group's Jeff Christian speaks with FS Insider to unpack the forces behind the explosive move in gold, silver, and other commodities. Christian explores the sustainability (or unsustainability)...

Jan 23, 2026 – Are we witnessing the end of the US dollar's bull run and a generational opportunity in commodities? In this insightful Smart Macro episode of the Financial Sense Newshour, Chris Puplava discusses the latest seismic shifts in...

Jan 23, 2026 – What's behind silver's explosive run past $100 an ounce and gold's push toward the $5,000 mark? Join host Jim Puplava for an in-depth interview with Bob Coleman, CEO of Idaho Armored Vaults, as they dive into the historic...

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Jan 21, 2026 – What surprises could catch investors off guard in 2026? In today's FS Insider interview, Jonathan Petersen, macro strategist at Variant Perception, walks through the firm's contrarian calls for the year ahead. From a long-awaited capex...

Jack Henris, President and COO, and Shawn Campbell, CFO of Dakota Gold (NYSE American: DC), both join me for a visual overview of the key 2025 initiatives achieved, and look ahead to the key exploration and development workstreams for 2026 that will feed into updated economics on their Richmond Hill Oxide Heap Leach Gold Project.  We also outline the long-term optionality of their Maitland Gold Project, which will also being receiving some exploration work and maiden resource this year.  Both projects are located in the historic Homestake District of South Dakota, near existing mining infrastructure.   Richmond Hill is one of the largest undeveloped oxide gold resources in the United States being advanced by a junior mining company, with over 6 million ounces of gold and over 60 million ounces of silver moving along the pathway of development into heap leach production as soon as 2029. Principle Projects are on Private Land which equates to a positive attribute for efficient permitting with State and County organizations.   The 2026 Richmond Hill drill campaign includes a total of 15,481 meters (50,790 feet) of drilling in 109 holes.   Infill drilling will convert inferred to measured and indicated resources for the initial 10 year mine plan area, expansion drilling will focus on the north Project area, and condemnation drilling will test areas for infrastructure suitability to ensure optimal site design for the Feasibility Study. All drilling required for the purpose of the Feasibility Study is expected to be completed by Q3 2026.     The Company will complete a Pre-Feasibility Study for Richmond Hill in the second half of 2026.   With the resource expansion drilling in the north intersecting significantly higher grades than resource cutoff. This resource drilling will be complimented with an extensive metallurgical test program, so that the Company will undertake a PFS with a focus on the first ten years of mining. This work will allow the Company to report reserves in 2026 and will inform the Feasibility Study to be completed in the first half of 2027.   The Company will launch a 2026 Maitland drill campaign of 5,578 meters (18,300 feet) in 44 holes.   The goal of this infill drilling, when combined with historic drill results, will be to define a maiden resource for the Tertiary-aged Unionville gold Zone.     Jack and Shawn highlight how these robust gold and silver resources, advantageous site infrastructure, and robust project economics, point to a future low-cost, long-life mining operation that can deliver high margins and generate meaningful revenues.   We review how the higher-grade mineralization that is being delineated through drilling in the northeast corner may accelerate the economics and shorten the payback period outlined in the SK 1300 Initial Assessment with Cash Flow from last year. We look at how higher underlying metals prices affect the economic sensitivities of this project in a major way. We review the potential for a rerating in valuation metrics when looked at through the lens of peer gold developer comparisons.   Click here to follow the latest news from Dakota Gold   If you have any questions for Jack or Shawn regarding Dakota Gold, then please email those in to me at Shad@kereport.com.   In full disclosure, Shad is a shareholder of Dakota Gold at the time of this recording, and may choose to buy or sell shares at any time.   For more market commentary & interview summaries, subscribe to our Substacks:   The KE Report: https://kereport.substack.com/ Shad's resource market commentary: https://excelsiorprosperity.substack.com/     Investment disclaimer: This content is for informational and educational purposes only and does not constitute investment advice, an offer, or a solicitation to buy or sell any security. Investing in equities and commodities involves risk, including the possible loss of principal. Do your own research and consult a licensed financial advisor before making any investment decisions. Guests and hosts may own shares in companies mentioned.      

Interview with Alex Dorsch, MD & CEO of Chalice MiningRecording date: 20th January 2026Chalice Mining is developing the Western world's leading palladium-nickel-copper project at Gonneville, discovered in 2020 near Perth, Australia. The project has advanced from discovery to prefeasibility study (PFS) stage, with Final Investment Decision (FID) and construction planned for 2028-29.The project's exceptional economics stem from open-pit mining starting at surface level, delivering all-in sustaining costs of $370/oz compared to $900-1,800/oz for South African competitors operating deep underground mines. This positions Gonneville in the second quartile of the global cost curve. The PFS demonstrates a 23-year mine life with NPV8 of A$3.3 billion at current prices and 40% IRR, producing 170,000 oz/year initially and scaling to 250,000 oz/year in stage two.Palladium prices have surged 105% from $880/oz to $1,800/oz over seven months, driven by supply constraints with over 90% production concentrated in Russia and South Africa. Demand remains resilient as electric vehicle adoption progresses slower than anticipated, supporting hybrid vehicles that require palladium catalytic converters.Chalice's two-stage development strategy balances ambition with capital discipline. Stage one requires A$820 million capex, fundable through 50-70% debt financing given strong project margins and abundant critical minerals financing from sovereign wealth providers. The company has invested A$325 million in technical work, including A$15 million on metallurgical testing—significantly more than typical junior miners at this stage.A simplified flowsheet redesign produces three standard products processable by conventional smelters, eliminating downstream technology risk. The project's Perth location provides infrastructure advantages and residential workforce access, reducing capital requirements to A$200-250 million versus multi-billion dollar bills for remote projects.With regulatory approvals expected in early 2028, Chalice offers rare exposure to palladium development outside Russian and South African dominance in a structurally constrained supply market.View Chalice Mining's company profile: https://www.cruxinvestor.com/companies/chalice-miningSign up for Crux Investor: https://cruxinvestor.com

[Audio section from Video on 01-21-2026]: Glenn Jessome, President & CEO of Silver Tiger Metals (TSX.V:SLVR) (OTCQX:SLVTF), joins me for a special video segment which visually unpacks the key metrics, maps, and forward-looking plan for the Preliminary Economic Assessment (PEA) for the underground mining second phase of the El Tigre Project.   We also review what the combined El Tigre Silver-Gold Project in Sonora, Mexico looks like on a valuation standpoint, when one sees the first phase surface mining stockwork zone in tandem with the underground second phase.     The bolt-on PEA is centered on the underground mining economics of the high-grade El Tigre, Sulphide, Black Shale and Seitz Kelly zones. The PEA mine design can be constructed independently of the Stockwork Zone development and is focused on the underground Mineral Resource. Prospective areas exist outside of the areas defined by the PEA and PFS with the historic “El Tigre North Mine” Mineral Resource located 700 metres to the North.   Highlights of the PEA , with a base case silver price of $38/oz and gold price of $3,200/oz are as follows (all figures in US dollars unless otherwise stated):   After-Tax net present value (“NPV”) (using a discount rate of 5%) of $304 million with an After-Tax IRR of 42.8% and Payback Period of 2.6 years (Base Case); 15-year UG mine life with 3-year historical tailings processing recovering a total of 38 million payable silver equivalent ounces (“AgEq”) or 453 thousand gold equivalent ounces (“AuEq”), consisting of 34 million silver ounces and 130 thousand gold ounces; Total Project undiscounted after-tax cash flow of $496 million; Initial capital costs of $83.5 million, including $10.9 million in contingency costs, over an expected 18-month build, and sustaining capital costs of $213 million over the life of mine (“LOM”); The 2026 PEA mine plan is designed as stand-alone to the PFS, with a potential overlap of initial capital cost of $17M (e.g., grid power, offices); Average LOM operating cash costs of $1,351/oz AuEq, and all in sustaining costs (“AISC”) of $2,019/oz AuEq or Average LOM operating cash costs of $16.05/oz AgEq, and AISC of $23.98/oz AgEq; Average annual production of approximately 2.3 million AgEq oz or 27.8 thousand AuEq oz, consisting of 2.1 million silver ounces and 8.0 thousand gold ounces (refer to Table 10 footnotes for conversion to Eq ozs); and PEA Study of the Southern Veins does not include the 38 million ounces AgEq contained in the Northern Veins (see details in updated Mineral Resource Estimate below).   We also go on to unpack all the #exploration upside still at surface, in the underground, and along the district-scale mineralized trend of a number of historic past-producing mines that will have drill programs for many years into the future.   If you have any follow up questions for Glenn regarding Silver Tiger Metals, then please email them into me at Shad@kereport.com.   In full disclosure, Shad is a shareholder of Silver Tiger Metals at the time of this recording, and may choose to buy or sell shares at any time.    Click here to follow the latest news from Silver Tiger Metals   For more market commentary & interview summaries, subscribe to our Substacks:   The KE Report: https://kereport.substack.com/ Shad's resource market commentary: https://excelsiorprosperity.substack.com/     Investment disclaimer: This content is for informational and educational purposes only and does not constitute investment advice, an offer, or a solicitation to buy or sell any security. Investing in equities and commodities involves risk, including the possible loss of principal. Do your own research and consult a licensed financial advisor before making any investment decisions. Guests and hosts may own shares in companies mentioned.      

Jan 19, 2026 – April 15 is fast approaching, but will your 2025 tax return bring a surprise refund or a painful bill? Jim Puplava sits down with tax expert Dan Pilla to decode the new "Big Beautiful Bill"...

Feeling overwhelmed by the rapid pace of change in multiple myeloma? ASH 2025 delivered potentially practice-changing data that could redefine second-line therapy and beyond. In this episode, we sat down with myeloma specialist Dr. Ben Derman from the University of Chicago to dissect the most critical studies. We moved from the controversial treatment of high-risk smoldering myeloma to head-to-head comparisons in newly diagnosed disease, and finally, to the groundbreaking bispecific antibody data that is set to revolutionize care at first relapse. Key topics covered in this episode: ● AQUILA update: Daratumumab in high-risk smoldering myeloma, and the ongoing clinical dilemma ● COBRA: Is KRD superior to VRD in newly diagnosed multiple myeloma? Unpacking the MRD and PFS data. ● TecLILLE: A first look at Teclistamab + Daratumumab in frontline, transplant-ineligible patients. ● MajesTEC-3: PFS and OS data for Teclistamab + Daratumumab in first relapse, and its impending FDA approval. Tune in for this expert breakdown to navigate the new myeloma landscape with confidence. Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Subscribe for more deep dives into treatment algorithms and major conference highlights! #OncologyBrothers #ASH2025 #MultipleMyeloma #Myeloma #SmolderingMyeloma #BispecificAntibody #Teclistamab #Daratumumab #CART

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Jan 13, 2026 – Global instability is rising, and Jacob Shapiro says the U.S. is responding with a bold strategic pivot. As power shifts to a multipolar world, America is retreating from global policing and refocusing on consolidating influence...

Jan 12, 2026 – Imagine transforming your home into a state-of-the-art wellness center—that's the future showcased at this year's Consumer Electronics Show. From AI-powered health devices and non-invasive wearables to personalized...

Today West Red Lake Gold Mines (TSXV: WRLG) declared commercial production at its Madsen Mine in Ontario. Mining Stock Daily interviewed Gwen Preston, VP communications, about the steps taken to reach to today's milestone. Gwen walks us through the "methodical approach" to ramp-up up milling operations.The conversation covered the following topics:Commercial Production Achieved: How WRLG exceeded their internal requirement (65% capacity for 30 days) by hitting 689 tpd (86%) in December. Madsen is permitted for 800 TPD. The Growth Strategy (PFS): A look ahead to the mid-year pre-feasibility study (PFS) which will combine Madsen, Fork, and the high-grade Rowan project.Macro Insights: Gwen shares her observations on the gold bull market and M&A.

In this episode of the Oncology Brothers podcast, we were joined by Dr. Julie Vose, a leading expert in lymphoma from the University of Nebraska Medical Center. Together, we delved into the key abstracts presented at ASH 2025, focusing on significant studies in lymphoma and chronic lymphocytic leukemia (CLL). Episode Highlights: ● EPCORE FL-1: the approval of Epcoritamab in combination with Rituximab and lenalidomide for relapsed refractory follicular lymphoma ● CLL-17: comparison between continuous BTK inhibitors and fixed-duration venetoclax with obinutuzumab ● BRUIN CLL-313: insights into the non-covalent BTK inhibitor, pirtobrutinib, and its effectiveness in the frontline setting compared to traditional treatments ● S1826: a three-year update on the use of Nivolumab-AVD versus BV-AVD in advanced-stage Hodgkin's lymphoma, showcasing improved PFS and better tolerability Join us as we unpack these practice-changing studies and discuss their implications for community oncologists. Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to subscribe for more insights and highlights from oncology conferences! #ASH25 #Oncology #Hematology #Lymphoma #CLL #CancerResearch

January 9, 2026 – What's in store for the markets and economy 2026? From wild market forecasts to the rise of AI CEOs and even regime changes, the 2026 outlook is packed with surprises. In our biggest show for the year, Jim Puplava dives into Wall Street...

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Mining Stock Daily welcomes back Leif Nilsson, CEO of Surge Copper, to discuss the advancing Berg project in Western British Columbia. With copper trading north of $5.00/lb and molybdenum showing strong sustained pricing, Surge is preparing a major milestone: a pre-feasibility study (PFS) slated for mid-2026.Key Topics Discussed:The 2026 PFS Roadmap: Timeline for delivery (targeting late March/early April) and expected improvements over the 2023 PEA.Scaling Up: The shift to a 120,000 tpd throughput model and the impact of new drilling on the resource model.Metallurgy & Economics: Updates on copper and molybdenum recoveries and how recent federal tax credits are influencing project economics.Infrastructure & Location: Differentiating Berg from the Golden Triangle—access via existing Forest Service Roads, proximity to grid power, and lower elevation logistics.Permitting: Preparing to formally enter the BC Environmental Assessment process and the support seen from the provincial Critical Minerals Office.The Macro Picture: Capital intensity trends and the M&A landscape for large-scale Canadian copper assets.Company InformationSurge Copper Corp. is a Canadian-based mineral exploration company focused on the acquisition, exploration, and development of mineral properties. The company owns a 100% interest in the Berg Project and the Ootsa Property in British Columbia.

Dr. Monty Pal and Dr. Hope Rugo discuss advances in antibody-drug conjugates for various breast cancer types as well as treatment strategies in the new era of oral SERDs for HR-positive breast cancer. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist and vice chair of academic affairs here at the City of Hope Comprehensive Cancer Center, Los Angeles. Today, I'm thrilled to be joined by Dr. Hope Rugo, an internationally renowned breast medical oncologist and my colleague here at City of Hope, where she leads the Women's Cancers Program and serves as division chief of breast medical oncology. Dr. Rugo is going to share with us exciting advances in antibody-drug conjugates (ADCs) that are expanding treatment options in various breast cancer types. She'll also address some of the complex questions arising in the new era of oral SERDs (selective estrogen receptor degraders) that are revolutionizing treatment in the hormone receptor-positive breast cancer space. Our full disclosures are available in the transcript of this episode.  Dr. Rugo, welcome, and thanks so much for being on the podcast today. Dr. Hope Rugo: Thank you. Pleasure to be here. Dr. Monty Pal: So, I'm going to switch to first names if you don't mind.  The first topic is actually a really exciting one, Hope, and this is antibody-drug conjugates. I don't know if I've ever shared this with you, but I actually started my training at UCLA, I was a med student and resident there, and it was in Dennis Slamon's lab. I worked very closely with Mark Pegram and a handful of others. This is right around the time I think a lot of HER2-directed therapies were really evolving initially in the clinics. Now we've got antibody-drug conjugates. Our audience is well-familiar with the mechanism there but tell us about how ADCs have really started to reshape therapy for HER2-positive breast cancer. Dr. Hope Rugo: Yeah, I mean, this is a really great place to start. I mean, we have had such major advances in breast cancer just this year, I think really changing the paradigm of treating patients. But HER2-positive disease, we've been used to having sequenced success of new agents. And I think the two biggest areas where we've made advances in HER2-positive disease, which were remarkably advanced this year in 2025, have been in antibody-drug conjugates with trastuzumab deruxtecan and with new oral tyrosine kinase inhibitors (TKIs) that have less of a target on EGFR and more on HER2, so they have an overall more tolerable toxicity profile and therefore a potentially better efficacy in the clinic. At least that's what we're seeing with these new strategies that we couldn't really pursue in the past because of toxicities of the oral TKIs. So, although our topic is ADCs, I'm going to include the TKI because it's so important in our thinking about treating HER2-positive disease. In the metastatic setting, we've seen these remarkable improvements in progression-free and overall survival in the second-line setting with T-DXd, or trastuzumab deruxtecan, compared to T-DM1. And then sequencing ADCs with giving T-DXd after T-DM1 was better than an oral tyrosine kinase or a trastuzumab combination with standard chemotherapy. That was DESTINY-Breast03 and DESTINY-Breast02. So, then we've had other trials since then, and T-DXd has moved into the early-stage setting, which I'll talk about in just a moment. But the next big trial for T-DXd in HER2-positive disease was moving it to the first-line setting to supplant what has become an established treatment for now quite a long time: the so-called CLEOPATRA regimen, which used the combined antibodies trastuzumab, pertuzumab with a taxane as first-line therapy. And then we've proceeded on with maintenance with ongoing HP for patients with responding or stable disease. And we'd seen long-term data showing, you know, at 8 years there was a group of patients whose cancers had never progressed and continued improved overall survival. So, T-DXd was studied in DESTINY-Breast09, either alone or in combination with pertuzumab compared to THP. The patient population had received a little bit more prior treatment, but interestingly, not a lot compared to CLEOPATRA. And they designed the trial to be T-DXd continued until progression with or without pertuzumab versus THP, which would go for six cycles and then stop around six cycles, and then stop and continue HP. Patients who had hormone receptor-positive disease could use hormone therapy, and this is one of the issues with this dataset because, surprisingly in this dataset and one other I'll mention, very few patients took hormone therapy. And even in the maintenance trial, the HER2CLIMB-05, less than 50% took hormone therapy as maintenance. This is kind of shocking to me and highlights an area of really important education, that outcome is improved when you add endocrine therapy for hormone receptor-positive HER2-positive metastatic disease in the maintenance phase, and it's a really important part of treatment. But suffice it to say, you know, you're kind of studying continued chemo versus stopping chemo in maintenance. And T-DXd, as we all expected, in combination with pertuzumab was superior to THP in terms of progression-free survival, really remarkably improved. And you could stop the chemo with toxicity, but most people continued it with T-DXd. Again, not a lot of people got hormone therapy, which is an issue, and you stop the chemo in the control arm. So, this has brought up a lot of interest in trying to use T-DXd as an induction and then go to maintenance, much as we do with the CLEOPATRA regimen with hormone therapy. But it brings up another issue. So first, T-DXd is superior; it's a great treatment. Not everybody needs to have it because we don't know whether it's better to give T-DXd first or second with progression - that we need a little bit longer follow-up. But just earlier this week, interestingly, the third week of December, the U.S. FDA approved T-DXd in the DESTINY-Breast09 approach with pertuzumab. So as I mentioned earlier, there was a T-DXd-alone arm; that arm has not yet reported. So very interesting, we don't know if you need pertuzumab or not. So what about the maintenance? That's the other area where we've made a huge advance here. So, we all want to stop chemo and we want to stop T-DXd. You don't want somebody being nauseated for two years while they're on treatment, and also there's a small number of patients with mostly de novo metastatic HER2-positive disease who are cured of their disease. We'd like to expand that, and I think these new drugs give us the opportunity to improve the number of patients who might be cured from metastatic disease. So the first maintenance study we saw was adding palbociclib, the CDK4/6 inhibitor, to endocrine therapy and HP, essentially. There, we had a remarkable improvement in progression-free survival difference of 15.2 months: 29 to 44 months, really huge. At San Antonio this year, we saw data with this oral tyrosine kinase inhibitor tucatinib, already showed it was great in a triplet, but as maintenance in combination with HP, it showed also a remarkable improvement in progression-free survival. But the numbers were all shifted down. So in PATINA, the control arm was in the 24-month range; here it was the tucatinib-HP arm that was in the 25 months and 16 months for control. So there was a differential benefit in ER-negative and ER-positive disease. So I think we're all thinking that our ideal approach moving forward would be to give T-DXd to most patients, we see how they do, and treat to best response. And then, stop the T-DXd, start HP, trastuzumab, pertuzumab for ER-negative, with tucatinib for ER-positive with palbociclib. We also have early data that suggests that both approaches may reduce the development of brain metastases, an issue in HER2-positive disease, and delay time to progression of brain metastases as seen in HER2CLIMB-05 in very early data - small numbers, but still quite intriguing that you might delay progression of brain metastases with tucatinib that clearly has efficacy in the brain.  So, I think that this is a hugely exciting advance for our patients, and these approaches are quickly moving into the early stage setting. T-DXd compared to standard chemo, essentially followed by THP, so a sequenced approach resulted in more pathologic complete responses than a standard THP-AC-type neoadjuvant therapy. T-DXd alone for eight cycles wasn't better, and that's interesting. We still need the sequenced non-cross-resistant chemo. But I think even more importantly, the data from DESTINY-Breast05 looking at T-DXd versus T-DM1 in patients with residual disease after neoadjuvant HER2-targeted therapy showed a remarkable improvement in invasive disease-free survival with T-DXd versus T-DM1, and quite early. It was a high-risk population, higher risk than the T-DM1 trial with KATHERINE, but earlier readout with a remarkable improvement in outcome. We expect to be FDA approved sometime in the first half of 2026. So then we'll get patients who've already had T-DXd who get metastatic disease. But my hope is that with T-DXd, maybe with tucatinib in the right group of patients or even sequenced in very high-risk disease, that we could cure many more patients with early-stage HER2-positive breast cancer and cure a subset, a greater subset of patients with de novo metastatic disease. Dr. Monty Pal: That's brilliant. And you tackled so many questions that I was going to follow up with there: brain metastases, etc. That was sort of looming in my mind. I mean, general thoughts on an ADC versus a TKI in the context of brain mets? Dr. Hope Rugo: Yeah, it's an interesting question because T-DXd has shown quite good efficacy in this setting. And tucatinib, of course, had a trial where they took patients with new brain mets, so a larger population than we've seen yet for the T-DXd trials, and saw that not only did they delay progression of brain metastases and result in shrinkage of existing untreated brain mets, but that patients who develop a new brain met, they could stay on the same assigned treatment. They got stereotactic radiation, and then the patients who were on tucatinib with trastuzumab and capecitabine had a further delay in progression of brain mets compared to those on the placebo arm, even after treatment of a new one that developed on treatment. So, I think it's hard. I think most of us for a lot of brain mets might start with the tucatinib approach, but T-DXd is also a very important treatment. You know, you're kind of trading off a diarrhea, some liver enzyme elevations with tucatinib versus nausea, which you really have to work on managing because it can be long-delayed nausea, and this risk of ILD, interstitial lung disease, that's about 12%, with most but not all trials showing a mortality rate from interstitial lung disease of just under 1 percent. In the early-stage setting, it was really interesting to see that with T-DXd getting four cycles in the neoadjuvant setting, a lot less ILD noted than the patients who got up to 14 cycles, as I think they got a median of 10 cycles in the post-surgical setting, there was a little bit more ILD. But I think we're going to be better and better at finding this earlier and preventing mortality by just stopping drug and treating earlier with steroids. Dr. Monty Pal: And this ILD issue, it always seems to resurface. There are drugs that I use in my kidney cancer clinic, everolimus, common to perhaps the breast cancer clinic as well, pembrolizumab, where I think the pattern of pneumonitis is quite different, right? What is your strategy for recognizing pneumonitis early in this context? Dr. Hope Rugo: Well, it is, and you know, having done the very early studies in everolimus where we gave it in the neoadjuvant setting and we're like, "Hmm, the patient came in with a cough. What's going on?" You know, we didn't know. And you have mouth sores, you know, we were learning about the drug as we were giving it. What we don't do with everolimus and CDK4/6 inhibitors, for example, is grade 1 changes like radiation pneumonitis, we don't stop, we don't treat it. We only treat for symptoms. But because of the mortality associated with T-DXd, albeit small, we stop drug for grade 1 imaging-only asymptomatic pneumonitis, and some of us treat with a half dose of steroids just to try and hasten recovery. We've actually now published or presented a couple of datasets from trials, a pooled analysis and a real-world analysis, that have looked at patients who were retreated after grade 1 pneumonitis or ILD and tolerated drug very well and none of them died of interstitial lung disease, which was really great to see because you can retreat safely and some of these patients stayed on for almost a year benefiting from treatment. So, there's a differential toxicity profile with these drugs and there are risk factors which clearly have identified those at higher risk: prior ILD, for example. A French group said smoking; other people haven't found that, maybe because they smoked more in France, I don't know. And being of Japanese descent is quite interesting. The studies just captured that you were treated in Japan, but I think it's probably being of Japanese descent with many drugs that increases your risk of ILD. And, you know, older patients, people who have hypoxia, those are the patients. So, how do we do this? With everolimus, we don't have specific monitoring. But for T-DXd we do; we do every nine weeks to start with and then every 12 weeks CT scans because most of the events occur relatively early. Somebody who's older and at higher risk now get the first CT at six weeks. Dr. Monty Pal: This is super helpful. And I have to tell you, a lot of these drugs are permeating the bladder cancer space which, you know, is ultimately going to be a component of my practice, so thank you for all this. We could probably stay on this topic of HER2-positive disease forever. I'm super interested in that space still. But let me shift gears a little bit and talk about triple-negative breast cancer and this evolving space of HR-positive, HER2-low breast cancer. I mean, tell us about ADCs in that very sort of other broad area. Dr. Hope Rugo: So triple-negative disease is the absolute hardest subset of disease that we have to treat because if you don't have a great response in the early stage setting, the median survival is very short, you know, under two years for the majority of TNBCs, with the exception of the small percentage of low proliferative disease subsets. The co-question is what do we do for these patients and how do we improve outcome? And sacituzumab govitecan has been one strategy in the later line setting that was shown to improve progression-free and overall survival, the Trop-2 ADC. We had recently three trials presented with the two ADCs, sacituzumab govitecan and the other Trop-2 ADC that's approved for HR-positive disease, datopotamab deruxtecan. And they were studied in the first-line setting. Two trials with SG, sacituzumab govitecan, those trials, one was PD-L1 positive, ASCENT-04. That showed that SG with a checkpoint inhibitor was superior, so pembrolizumab was superior to the standard KEYNOTE-355 type of treatment with either a taxane or gemcitabine and carboplatin with pembrolizumab for patients who have a combined positive score for PD-L1, 10 or greater. So, these are patients who are eligible for a checkpoint inhibitor, and SG resulted in an improved progression-free survival.  The interesting thing about that dataset is that few patients had received adjuvant or neoadjuvant checkpoint inhibitor, which is fascinating because we give it to everybody now. But access is an issue and timing of the study enrollment was an issue. The other thing which I think we've all really applauded Gilead for is that there was automatic crossover. So, you could get from the company, to try and overcome some of the enormous disparities worldwide in access to these life-saving drugs, you could get SG through the company for free once you had blinded independent central review confirmation of disease progression. Now, a lot of the people who got the SG got it through their insurance, they didn't bill the company, but 80 percent of patients in the control arm received SG in the second-line setting. So that impacts your ability to look at overall survival, but it's an incredibly important component of these trials. So then at ESMO, we saw the data from SG and Dato-DXd in the first-line metastatic setting for patients who either had PD-L1-negative disease or weren't eligible for an immunotherapy. For the Dato study, TROPION-Breast02, that was 10 percent of the patients who had PD-L1-positive disease but didn't get a checkpoint inhibitor, and for the ASCENT-03 trial population it was only 1 percent. Importantly, the trials allowed patients who relapsed within a year of receiving their treatment with curative intent, and the Dato study, TB-02, allowed patients who relapsed while on treatment or within the first six months, and that was 15 percent of the 20 percent of early relapsers. The ASCENT trial, ASCENT-03, had 20 percent who relapsed between 6 and 12 months. The drugs were better than standard of care chemotherapy, the ADCs in both trials, which is very nice. Different toxicity profiles, different dosing intervals, but better than standard of care chemotherapy in the disease that's hardest for us to treat. And importantly, when you looked at the subset of early relapsers, those patients also did better with the ADC versus chemotherapy, which is incredibly important. And we were really interested in that 15 percent of patients who had early relapse. I actually think that six months thing was totally contrived, invented, you know, categorization and doesn't make any sense, and we should drop it. But the early relapsers were 15 percent of TB-02 and Dato was superior to standard of care chemo. We like survival, but the ASCENT trial again allowed the crossover to an approved ADC that improved survival and 80 percent of patients crossed over. In the Dato trial, they did not allow crossover, they didn't provide Dato, which isn't approved for TNBC but is for HR-positive disease, and they didn't allow, of course, pay for SG. So very few patients actually crossed over in their post-treatment data and in that study, they were able to show a survival benefit. So actually, I think in the U.S. where we can use approved drugs already before there's a fixed FDA approval, that people are already switching to use SG or Dato in the first-line setting for metastatic TNBC that's both PD-L1 positive for SG and PD-L1 negative for both drugs. And I think understanding the toxicity profiles of the two drugs is really important as well as the dosing interval to try and figure out which drug to use. Dr. Monty Pal: Brilliant. Brilliant. Well, I'm going to shift gears a little bit. ADCs are a topic, again, just like HER2-positive disease we could stay on forever. Dr. Hope Rugo: Huge. Yes. Dr. Monty Pal: But we're going to shift gears to another massive topic, which is oral SERDs. In broad strokes, right, this utilization of CDK4/6 inhibitors in the context of HR-positive breast cancer is obviously, you know, a paradigm that's been well established at this point. Where do we sequence in oral SERDs? Where do they fit into this paradigm? Dr. Hope Rugo: Ha! This is a rapidly changing area; we keep changing what we're saying every other minute. And I think that there are three areas of great interest. So one is patients who develop ESR1 mutations that allow constitutive signaling through the estrogen receptor, even when there's not estrogen around, and that is a really important mutation that is subclonal; it develops under the pressure of treatment in about 40 percent of patients. And it doesn't happen when you first walk in the door. And what we've seen is that oral SERDs as single agents are better than standard single-agent endocrine therapy in that setting. The problem that we've had with that approach is that we're now really interested in giving targeted agents with our endocrine therapies, not just in the first-line setting where CDK4/6 inhibitors are our standard of care with survival benefit for ribociclib and, you know, survival benefit in subsets with other CDK4/6 inhibitors, and abemaciclib with a numeric improvement. So we give it first line. The question is, what do you do in the second-line setting? Because of the recent data, we now believe that oral SERDs should be really given with a targeted agent. And some datasets which were recently presented, which I think have helped us with that, have been EMBER-3 and then the most recently evERA BC, or evERA Breast Cancer, that looked at the oral SERD giredestrant with everolimus compared to standard of care endocrine therapy with everolimus, where 100 percent of patients received prior CDK4/6 inhibitor and showed a marked improvement in progression-free survival, including in the subsets of patients with a short response, 6-12 months of prior response to CDK4/6 inhibitor and in those who had a PIK3CA pathway mutation. The thing is that the benefit looks like it's much bigger in the ESR1 mutant population, although response was better, PFS wasn't better in the wild type. So, we're still trying to figure that out. We also saw EMBER-3 with imlunestrant and abemaciclib as a second line. Not everybody had had a prior CDK4/6 inhibitor; they compared it to imlunestrant alone, but still the data was quite striking and seemed to cross the need for ESR1 mutations. And then lastly, we saw data from the single arms of the ELEVATE trial looking at elacestrant with everolimus and abemaciclib and showed these really marked progression-free survival data, even though single-arm, that crossed the mutation status. At least for the everolimus combination, abemaciclib analysis is still to come in the mutated subgroups. But really remarkable PFS, much longer.  Single-agent fulvestrant after CDK4/6 inhibitor AI has a PFS in like the three-month range and in some studies, maybe close to five months. These are all at 10-plus months and really looking very good. And so those questions are, is it ESR1 mutation alone? Is it all comers? We'd like all comers, right? We believe in the combination approach and we're learning more about combinations with drugs like capivasertib and other drugs as we move forward. Everybody now wants to combine their targeted agent with an oral SERD because they're clearly here to stay with quite remarkable data. The other issue, so the second issue in the metastatic setting is, does it make a difference if we change to an oral SERD before radiographic imaging evidence of progression? And that was the question asked in the SERENA-6 trial where patients had serial monitoring for the presence of ESR1 mutations in ctDNA. And those who had them without progression on imaging could be randomized to switch to camizestrant with the same CDK4/6 inhibitor or stay on their same AI CDK4/6 inhibitor. And they showed a difference in progression-free survival that markedly favored camizestrant. But interestingly, the people who were on the standard control arm had an ESR1 mutation, we think AIs don't work, they stayed on for nine more months. The patients who were on the camizestrant stayed on for more than 16 months. And they presented some additional subset data which showed the same thing: follow-up PFS data, PFS2, all beneficial in SERENA-6 at the San Antonio [Breast Cancer Symposium]. So, we're still a little bit unclear about that. They did quality of life, and pain was markedly improved. They had a marked delayed time to progression of pain in the camizestrant arm. So this is all a work in progress, trying to understand who should we switch without progression to an oral SERD based on this development of this mutation that correlates with resistance. And, you know, it's interesting because the median time to having a mutation was 18 months and the median time to switch was almost 24 months. And then there were like more than 3,000 patients who hadn't gotten a mutation, hadn't switched, and were still okay. So screening everybody is the big question, and when you would start and who you would change on and how this affects outcome. Patients didn't have access to camizestrant in the control arm, something we can't fix but we have experimental drugs. We're actually planning a trial, I hope in collaboration with the French group Unicancer, and looking at this exact question. You know, if you switch and you change the CDK4/6 inhibitor and then you also allow crossover, what will we see? Dr. Monty Pal: We're coming right to the tail end of our time here, and I could probably go on for another couple of hours with you here. But if you could just give us maybe one or two big highlights from San Antonio, any thoughts to leave our audience with here based on this recent meeting? Dr. Hope Rugo: Yeah, I mean, I talked about a lot of those new data already from San Antonio, and the one that I'd really like to mention which I think was, you know, there were a lot of great presentations including personalized screening presented from the WISDOM trial by my colleague Laura Esserman, fascinating and really a big advance. But lidERA was the big highlight, I think, outside of the HER2CLIMB-05 which I talked about earlier in HER2-positive disease. And this study looked at giredestrant, the oral SERD versus standard of care endocrine therapy as treatment for medium and high-risk early-stage breast cancer. And what they showed, which I think was really remarkable with just about a three-year median follow-up, was an improvement in invasive disease-free survival with a hazard ratio of 0.7. I mean, really quite remarkable and so early. It looked as though this was all driven by the high-risk group, which makes sense, not the medium risk, it's too early. And also that there was a bigger benefit in patients who were on tamoxifen compared to giredestrant versus AI, but for both groups, the confidence intervals didn't cross 1. There's even a trend towards overall survival, even though it's way too early. I think that, you know, really well-tolerated oral drug that could improve outcome in early-stage disease, this is the first advance we've seen in over two decades in the treatment of early-stage hormone receptor-positive disease with just endocrine therapy. I think we think that we don't want to give up CDK4/6 inhibitors because we saw a survival benefit with abemaciclib and a trend with giving ribociclib in the NATALEE trial. So we're thinking that maybe one approach would be to give CDK4/6 inhibitors and then switch to an oral SERD or to have enough data to be able to give oral SERDs with these CDK4/6 inhibitors for early-stage disease. And that's all in the works, you know, lots of studies going on. We're going to see a lot of data with both switching 8,000 patients with an imlunestrant switching trial, an elacestrant trial going on, and safety data with giredestrant with abemaciclib and soon to come ribociclib. So, this is going to change everything for the treatment of early-stage breast cancer, and I hope cure more patients of the most common subset of the most common cancer diagnosed in women worldwide. Dr. Monty Pal: Super exciting. It's just remarkable to hear how this has evolved since 25 years ago, which is really the last time I sort of dabbled in breast cancer.  Thank you so much, Hope, for joining us today. These were fantastic insights. Appreciate you being on the ASCO Daily News Podcast and really want to thank you personally for your remarkable contribution to the field of breast cancer. Dr. Hope Rugo: Thank you very much, and thanks for talking with me today. Dr. Monty Pal: You got it. And thanks a lot to our listeners today as well. You'll find links to all the studies we discussed today in the transcript of this episode. Finally, if you value the insights that you hear today on the ASCO Daily News Podcast, please rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinion of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:   Dr. Monty Pal @montypal Dr. Hope Rugo   @hoperugo Follow ASCO on social media:        ASCO on X  ASCO on Bluesky       ASCO on Facebook        ASCO on LinkedIn        Disclosures:     Dr. Monty Pal:    Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview   Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical   Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis   Dr. Hope Rugo:    Honoraria: Mylan/Viatris, Chugai Pharma   Consulting/Advisory Role: Napo Pharmaceuticals, Sanofi, Bristol Myer   Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Hoffman La-Roche AG/Genentech, In., Stemline Therapeutics, Ambryx  

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