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mCRPC Synergy Series: Overcoming Resistance and Optimizing Pathways | Part 1: Decoding Resistance Biology

Clinical oncology
Medical oncology
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Description

This program is supported by an independent educational grant from Pfizer. This education program is available to healthcare professionals globally.

This is Part 1 of a four-part on-demand series.

Join prostate cancer experts Dr. Michael Schweizer and Dr. Emmanuel Antonarakis for this accredited, interactive teaching session focused on the latest updates for 2026 in overcoming treatment resistance and optimizing therapeutic pathways in metastatic castration-resistant prostate cancer (mCRPC). Through real-world cases and expert-led discussion, faculty will translate emerging evidence into practical strategies to support sequencing decisions after AR pathway inhibitor (ARPI) progression. This program also includes an interview with a patient advocate from Zero Prostate Cancer, Darrell Wilson.

Credits: AMA PRA Category 1 Credits™ (0.25.00 hours)

Session Overview

Overcoming Resistance and Optimizing Pathways

This case-based session explores how evolving insights into resistance biology can inform more precise, personalized treatment decisions in mCRPC. Faculty will guide learners through common clinical scenarios encountered after ARPI progression, highlighting how biomarkers, emerging mechanisms, and novel non-chemotherapy approaches may shape next steps in care.

  • Review emerging insights into resistance biology beyond DNA repair, including lineage plasticity, AR co-activation, and epigenetic dysregulation, and how these concepts are influencing contemporary mCRPC thinking
  • Discuss the growing translational rationale for targeting epigenetic pathways such as EZH2, including current evidence gaps and implications for future practice
  • Compare novel non-chemotherapy approaches—including radioligand therapies, antibody–drug conjugates, and immunotherapies—and where these modalities may fit within emerging treatment paradigms

Who Should Attend?

This program is designed for healthcare professionals globally involved in the diagnosis, treatment selection, and ongoing management of patients with mCRPC, including:

  • Medical and radiation oncologists
  • Urologists
  • Oncology nurses and nurse practitioners
  • Physician assistants
  • Pharmacists
  • Others involved in prostate cancer care

Faculty

Emmanuel Antonarakis, M.D. is an internationally recognized prostate cancer expert and clinician-scientist with extensive experience in resistance biology, biomarker-driven treatment selection, and translational research guiding precision approaches in mCRPC.

Michael Schweizer, M.D. is a medical oncologist specializing in genitourinary cancers with expertise in advanced prostate cancer, resistance mechanisms, and clinical trials evaluating novel therapeutic strategies in mCRPC.

Darrell Wilson is a patient advocate representing Zero Prostate Cancer.

Program Schedule

Part 1: Decoding Resistance Biology (Current Module)

Apply knowledge of ARPI resistance mechanisms, including epigenetic dysregulation and lineage plasticity, to inform clinical decision-making in mCRPC.

Part 2: Sequencing After ARPI

Formulate and implement evidence-based sequencing strategies for patients progressing on a first-line ARPI, incorporating genomic biomarkers and advanced imaging into individualized treatment plans.

Please click here to access Part 2.

Part 3: Epigenetic Rationale

Incorporate the rationale for targeting epigenetic pathways into treatment planning to extend the clinical benefit of AR-directed therapy in mCRPC.

Please click here to access Part 3.

Part 4: Emerging Non-Chemo Options

Differentiate and apply understanding of mechanisms of action of emerging non-chemotherapy agents, including radioligands, antibody-drug conjugates, and immunotherapies, to guide therapy selection.

Please click here to access Part 4.

Interview with Patient Advocate

Please click here to access the Patient Advocate interview.

Continuing Education Information

Commercial support: This activity received monetary support through an independent education grant from Pfizer.

This continuing education activity will be provided by AffinityCE and MedAll. This activity will provide continuing education credit for physicians. A statement of participation is available to other attendees.

Faculty Disclosure Statement / Conflict of Interest

Emmanuel Antonarakis, MD, has disclosed financial interests or relationships within the past 24 months with the following ineligible companies: Advisory Board/Consultant for Abeona Therapeutics, AstraZeneca, Bayer, DAVA Oncology, EcoR1, Janssen, Johnson & Johnson, Lilly, Merck, MJH Life Sciences, Pfizer, Tango Therapeutics, Tempus, The Medical Educator Consortium, z-Alpha. Grant/Research Support from Bayer, Bristol-Myers Squibb, Clovis, MacroGenics, Merck, Novartis, Orion, Seagen. Honoraria for Binaytara, ClearView, Curium, Fred Hutch Cancer Center, Healthcare Partners, Lilly, Merck. These disclosures are provided in accordance with ACCME standards to ensure transparency and uphold the integrity of continuing education. Dr. Antonarakis does not intend to reference any unlabeled or unapproved uses of products during the presentation.

Michael Schweizer, MD, has disclosed financial interests or relationships within the past 24 months with the following ineligible companies: Advisory Board for Daiichi Sankyo, Fibrogen, J&J, Pfizer, Consultant for Bayer, K36 Therapeutics, Grant/Research Support from Ambrx, AstraZeneca, BMS, Epigenetix, J&J, Lightspeed, Merck, Novartis, Oric Pharmaceuticals, Pfizer, Xencor, Zenith Epigenetics.These disclosures are provided in accordance with ACCME standards to ensure transparency and uphold the integrity of continuing education. Dr. Schweizer does intend to reference unlabeled or unapproved uses of products during the presentation.

Darrell Wilson has disclosed financial interests or relationships within the past 24 months with the following ineligible companies: Patient perspective involvement for Sandoz, Novartis, Pfizer.

AffinityCE staff, MedAll staff, as well as planners and reviewers, have no relevant financial relationships with ineligible companies to disclose.

In compliance with EBAC guidelines, all speakers/ chairpersons participating in this programme have disclosed or indicated potential conflicts of interest which might cause a bias in the presentations. The Organizing Committee/Course Director is responsible for ensuring that all potential conflicts of interest relevant to the event are declared to the audience prior to the CE activities.

Mitigation of Relevant Financial Relationships

AffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible companies. Relevant financial relationships were mitigated by the peer review of content by non-conflicted reviewers prior to the commencement of the program.

Activity Accreditation for Health Professions

Physicians

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and MedAll. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.

AffinityCE designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Physician Assistants

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and MedAll. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.

AffinityCE designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physician assistants should claim only the credit commensurate with the extent of their participation in the activity.

Nurse Practitioners

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and MedAll. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.

AffinityCE designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Nurse practitioners should claim only the credit commensurate with the extent of their participation in the activity.

Nurses & Other Professionals

All other health care professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity.

EBAC® CME Information

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the European Board for Accreditation of Continuing Education for Health Professionals (EBAC)

MedAll is an EBAC accredited provider since 2025. The European Board for Accreditation of Continuing Education for Health Professionals (EBAC) accredits Continuing Education (CE) programmes for the international medical community.

This program is accredited by the European Board for Accreditation of Continuing Education for Health Professionals (EBAC®) for 15 minutes of effective education time.

EBAC® holds an agreement on mutual recognition of substantive equivalency with the US Accreditation Council for CME (ACCME) and the Royal College of Physicians and Surgeons of Canada, respectively.

Through an agreement between the European Board for Accreditation of Continuing Education for Health Professionals (EBAC®) and the American Medical Association, physicians may convert EBAC® External CME credits to AMA PRA Category 1 Credits. Information on the process to convert EBAC® credit to AMA credit can be found on the AMA website. Other healthcare professionals may obtain from the AMA a certificate of participation in an activity eligible for conversion of credit to AMA PRA Category 1 Credit.

The Accreditation Council for Continuing Medical Education (ACCME) and the Royal College of Physicians and Surgeons of Canada hold an agreement on substantial equivalency of accreditation systems with EBAC.

EBAC® is a member of the International Academy for CPD Accreditation (IACPDA) and a partner member of the International Association of Medical Regulatory Authorities (IAMRA).

System Requirements

Mobile device (e.g., large-format smart phone; laptop or tablet computer) or desktop computer with a video display of at least 1024 × 768 pixels at 24-bit color depth, capable of connecting to the Internet at broadband or faster speeds, with a current version Internet browser and popular document viewing software (e.g., Microsoft Office, PDF viewer, image viewer) installed. Support for streaming or downloadable audio-visual materials (e.g., streaming MP4, MP3 audio) in hardware and software may be required to view, review, or participate in portions of the program.

Unapproved and/or off-label use disclosure

AffinityCE/MedAll requires CE faculty to disclose to the participants:

  • When products or procedures being discussed are off-label, unlabeled, experimental, and/or investigational (not US Food and Drug Administration [FDA] approved); and
  • Any limitations on the information presented, such as data that are preliminary or that represent ongoing research, interim analyses, and/or unsupported opinion.

CME Inquiries

For all CME policy-related inquiries, please contact us at ce@affinityced.com.

Participation Costs

There is no cost to participate in this program.

Requirements for Completion

To receive credit, participants must complete the full activity, the post-test, and the evaluation form before the stated expiration date. There are no prerequisites, and there is no fee to participate or claim credit. A Certificate of Completion will be issued upon successful completion of all required components.

A minimum passing score of 70% on the post-test is required. Participants should consult their own professional licensing authority regarding eligibility to claim credit for this educational activity.

EBAC® only awards CE certificates in increments of 1.0 credit.

Launch and Expiration Date: 2 March 2026 – 20 February 2028

Estimated time to complete this activity: 15 minutes

Disclaimer

This activity is intended for educational purposes only and does not establish a standard of care or replace clinical judgment. Any therapeutic or diagnostic strategies discussed must be evaluated in the context of each patient’s clinical circumstances, risks, and current evidence.

Learners should consult authoritative clinical guidelines and approved product information when considering treatment decisions.

All materials are used with permission. The views expressed are those of the faculty and do not necessarily reflect those of the accredited providers, MedAll, or any supporters.

Content is accurate as of the date of release.

Learning objectives

By the end of this session participants will be better able to:

  • Apply knowledge of ARPI resistance mechanisms, including epigenetic dysregulation and lineage plasticity, to inform clinical decision-making in mCRPC.
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Computer generated transcript

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The following transcript was generated automatically from the content and has not been checked or corrected manually.

Thanks for joining us today. Uh, I'm, my name is Michael Schweitzer. I'm a faculty member here at the Fred Hutchinson Cancer Center at University of Washington in Seattle. Um, today, I'm gonna be talking about receptor pathway inhibitor resistance. Here are my disclosures. And the learning objective for this talk is to really learn how to apply knowledge of angioreceptor pathway inhibitor resistance mechanisms, including epigenetic dysregulation and lineage plasticity to inform clinical decision making in metastatic castrate resistant prostate cancer or MCRPC. Let's start with a case-based vignette. So, this is a 68-year-old man with a history of metastatic prostate cancer who presents for follow-up. He's been on treatment with leuprolide and abiraterone for 3 years now and has recently been noted to have a rising PSA. PSA trend has gone from 0.8 to 2.3 and now 8 nanograms per mL over the past three months. Conventional imaging reveals several new osseous metastases and enlarging lymphadenopathy. You obtained somatic next-generation sequencing, what is the most likely finding? A, AR amplification, B, AR ligand binding domain mutation, C, BRCA2 mutation, or D, evidence of mismatch repair deficiency. OK. We'll circle back to that at the, at the end of the talk. Prostate cancer is often conceptualized along a disease continuum. If you imagine most patients presenting on the left-hand part of this figure with low tumor volume and low PSAs, these are the patients who are typically cured with local treatments, including surgery or radiation-based therapies. However, uh, a number of patients do present with metastatic disease at baseline or subsequently relapse after local therapies. It's at this point that we think about adding androgen deprivation therapy or ADT and most often combine it with uh one of the anti-receptor pathway inhibitors, including drugs like enzalutamide or abiraterone. Uh, we also have data suggesting that there are some patients who likely benefit from the addition of docetaxel chemotherapy, and patients who have select mutations and genes involved in homologous or combination repair are now also candidates to receive uh abiraterone in combination with the PARP inhibitor, nerarib. These, uh, agents tend to work very well initially, uh, which is why we termed this stage of the disease hormone-sensitive prostate cancer. However, uh, patients will generally relapse at some point, at which time we say that they've transitioned to the castration resistant form of the disease, which tends to be more aggressive and ultimately lethal. It's at this stage that we think about cycling through any number of other therapies that are currently approved in this setting, which I've listed on the right-hand part of the screen. It's worth noting, however, that while we always use ADT as part of our treatment and typically combine it with an interoceptor pathway inhibitor, these drugs are also used for some patients in the cast resistant setting, and cross-resistance between these agents really limits their efficacy when used in the second-line setting. Case in point is retrospective data from a number of series looking at second-line responses to either abiraterone or enzalutamide. So on the top here, these are patients who received abiraterone after previously progressing on enzalutamide, and the bottom rows are patients who received enzalutamide after abiraterone. Note that the PSA response rates are relatively modest with these, with less than 10% of patients responding to abiraterone second line, and between 20 to 30% of patients typically having a PSA response to enzalutamide in this setting. A phase two, prospective study evaluated the optimal sequence of abiraterone followed by enzalutamide as compared to enzalutamide followed by abiraterone. In this study, they wanted to look at the time to second progression, that is progressing after the second-line agent or PFS2, uh, as well as look at the PSA responses to the second-line agent itself. The figure on the right here shows the second line responses to either enzalutamide on the left or abiraterone on the right, and you can see that overall the second line responses are quite modest with each of these drugs, with enzalutamide noting a decline in PSA of 30% or more from baseline in 36% of patients, while with abiraterone it was only 4% of patients had this degree of PSA response observed. They did show that in terms of PFS2, that the time to the second progression event was longer in patients who got the sequence of abiraterone followed by enzalutamide as compared to enzalutamide followed by abiraterone. Of note, however, there was no difference in overall survival between these two arms, although the study was not powered to look at survival. Let's pause and go for another polling question. Which of the following best describes a recognized mechanism of resistance to ARPI therapies that reflects lineage plasticity rather than AR dependent signaling? A, increased ECH2 mediated epigenetic reprogramming. B, upregulation of SIP 17 mediated androgen synthesis. C, enhanced AR nuclear translocation. D, increased AR coactivator binding, or stabilization of AR protein to reduced degradation. All right, let's move on. Regarding the mechanisms that drive resistance between the anti-receptor pathway inhibitors, it's important to note that there's a variety of different ones out there, and there's a large body of literature describing the various mechanisms at play. It's beyond the scope of this talk to go into each of these in detail, but broadly, I think of classifying these into 3 different groups. Those that are receptor activating, these would be uh things like angio receptor ligand binding to mut mutations which can convert angio receptor antagonists into agonists or be activated by alternative steroids. Angioreceptor splice variants that don't need the ligand to be activated and angioreceptor amplifications. There are also non-angiogen receptor-dependent oncogenic pathways that can drive tumor growth. These would be things like loss of tumor suppressor genes, which can lead to hyperproliferative states or alternative sequing pathways such as PI3 kinase signaling. And then there's lineage plasticity, the switching of phenotypes that the tumor no longer relies on angiogen receptor to drive its growth in the first place. Highlighting the degree of heterogeneity that we see, this landscape figure from the International Dream Team Stand Up to Cancer paper shows that there's a number of different mutations that are observed in the metastatic castrate resistant setting. This study involved metastatic biopsies from patients who were on developed metastatic castrate resistant prostate cancer and underwent molecular profiling as the As the onco print on the left shows, there's a variety of different mutations that have been noted in this study, and broadly, this paper classified them as being WI pathway signaling, PA3 kinase pathway alterations, AR pathway alterations, those involved in DNA repair, such as those uh critical to homologous or combination repair, and those uh result in cell cycle aberrations such as RB1 alterations. Again, this is just one paper showing a snapshot of the various mutations we see and several other publications looking at these in more detail have already been published. Also looking at the heterogeneity uh that we see in later-stage cancer resistant prostate cancer is work from the University of Washington Rapid Autopsy Program. In this study, they, uh, defined tumors as being anti receptor positive or neuroendocrine positive based on immunohistochemistry. And you can see that when they perform a transcriptional uh profiling on these tumors, that it does a good job in terms of segregating, uh, the different subtypes that we see in late-stage prostate cancer. So, what exactly is lineage plasticity? This is essentially phenotype switching that occurs most often in the context of chronic angioreceptor pathway inhibition. This can drive the loss of luminal markers that we typically see at diagnosis, those involved in angio receptor signaling and air dependence, and lead to the acquisition of alternative lineage programs, including those related to neuroendocrine prostate cancers. Uh, it's notable that there's been an increasing incidence of antireceptor null prostate cancers that have been observed since the approval of abiraterone, the first of the next-generation antireceptor pathway inhibitors to be developed. On the right here is a figure that shows, uh, the, the incidence of angioreceptor negative prostate cancers in both the pre-abiraterone setting in the left and the post-abbiraterone setting on the right. I'll just draw your attention to the top panel where we see that. In the pre-Abiraterone setting, approximately 10 to 11% of patients who died of prostate cancer had evidence of an ARNL tumor. Whereas in the post-Abiraterone setting, we see that it's approximately 1/3 of all patients who die from prostate cancer have evidence of an AR negative prostate cancer in that setting, really speaking to the idea that we are pushing tumors towards these ARL phenotypes and promoting lineage plasticity through the use of these AR signaling inhibitors. There's a lot of work that's gone into understanding the biology that leads to lineage plasticity and the loss of these error markers, but a basic model of lineage plasticity that pertains to prostate cancer includes a number of key molecular events, including genomic loss of RB1 and T53, which can facilitate the shift away from the lunar phenotype. Further dysregulation of oncogenic drivers and lineage determined transcription factors, facilitates this transition further. And then finally, epigenetic changes, including increased EZH2. Activity can lead to these tumors losing AR luminal markers and developing these alternative lineages such as neuroendocrine prostate cancers. Given the phenotypic diversity of late stage metastatic castrate resistant prostate cancer, a system for classifying prostate cancer subtypes subtypes based on AR and neuroendocrine immunohistochemistry markers has recently been proposed. This provides a framework for which we can define prostate cancers and in turn systematically evaluate therapeutic strategies tailored to each subset. So returning to our case-based vignette, uh, overall, uh, of the four answers provided, uh, AR amplification is the most commonly seen, uh, molecular change that we see out of the ones listed. And again, just looking back at this landscape figure from the International Dream Team Work from Center to Cancer, you can see that overall, over 60% of patients