This site is intended for healthcare professionals

mCRPC Synergy Series: Overcoming Resistance and Optimizing Pathways | Part 3: Epigenetic Rationale

Clinical oncology

Medical oncology

Claim CME credit

Share

Description

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

This is Part 3 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

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

Please click here to access Part 1.

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 (Current Module)

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

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:

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

Claim CME credit

Similar communities

Similar events and on demand videos

Claim CME credit

Computer generated transcript

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

And today, I'm gonna be talking about the rationale for targeting epigenetic pathways in prostate cancer. The learning objectives for this, uh, presentation is to incorporate the rationale for targeting epigenetic pathways into treatment planning to extend the clinical benefit of AR directed therapy in metastatic castor-resistant prostate cancer. First, let's start with a polling question. In patients with metastatic castorismant prostate cancer who progress after AR-directed therapy and radioligand therapy, which finding would most strongly suggest that epigenetic reprogramming may be contributing to treatment resistance? A high PSA but stable imaging. B, disease progression with low stable PSA, C, low volume bone-only disease, D, presence of temperIE effusions, or E, prior response to docetaxel. OK. Let's dive into a case-based vignette. So, Mr. Jay is a 72-year-old man with metastatic prostate cancer with osseous and hepatic metastasis. He was initially treated with leuprolide plus dalutamide and now appears to be progressing after lutician PSMA 617. Recent liver biopsies consistent with prostatic adenocarcinoma, and immunohistochemistry shows expression of NKX 3.1 and INSM1 is negative. Somatic sequencing reveals a TP53 mutation, AR amplification, and a tempersu-ERG fusion. What's his next best line of treatment? A docetaxel plus carboplatin, B abiraterone, C clinical trial testing of pure C2 or ECH2 inhibitor plus an angio receptor pathway inhibitor, or D, cabazitaxel. All right, we'll come back to this one at the end of the talk. So, there's a large body of literature to describe 100s of different enzymes evolved in regulating the epigenome. These include those that methylate CPG islands. These typically lead to gene silencing, those that acetylate histones, which oftentimes leads to open chromatin and activating genes, histomethylation effects, which can be more diverse and can lead to both, uh, turning genes on or off. Key epigenetic modifications have been uh further classified as uh being writers, which can add modifications including DNA methyl transferases or EZH2, erasers which can remove modifications such as histone deacetylases, readers which can recognize and read methyl and acetyl marks. These would include the bromidoin proteins and movers such as E1A, which can remodel chromatin. Uh, by moving along nucleosomes. Importantly, epigenetic dysregulation has been shown to be a key driver of lineage plasticity and resistant prostate cancers. Two of the ones that are best well described in uh metastatic castrate resistant prostate cancer include alterations in EZH2 methylation and uh bromine protein activity. I'll focus on EZH2 as a target, since that's the furthest developed in terms of uh therapeutic, uh, Uh, strategies in prostate cancer. Interestingly, when we look at both anti receptor-positive prostate cancers and neuroendocrine-po prostate cancers, you can see that from a genomic standpoint, that there's really a number of similarities between these, these different cases, whereby the mutations that are observed are fairly similar between those that are AR or neuroendocrine positive. Interestingly, however, genome-wide DNA methylation analysis reveals really marked epigenetic differences between the neuroendocrine and the AR positive cases. Suggesting that epigenetic modifications may play a role in induction or maintenance of this treatment resistant state. Further, hierarchical clustering of this data shows that uh epigenetic differences between the A and neuroendocrine prostate cancers does a good job at clustering them together. Of note, 3 cases from this, uh, study revealed that Uh, AR positive cases clustered with the neuroendocrine ones. And when you look at the clinical histories of these, it's notable that many of these have lower PSA values and visceral disease, which is often noted to be a clinical sign of lineage plasticity and a loss of air dependence. Higher, uh, functional enrichment analysis further showed that a number of differentially methylated genes identified multiple epigenetically dysregulated pathways that are relevant for neuroendocrine biology, including those involved in epithelial mesenchymal transition, cell cell adhesion, and, uh, stem cell programs. Let's pause for another polling question. Which of the best describes how ECH2 contributes to resistance in advanced prostate cancer? A increases androgen production, B enhances AR nuclear activity, C, boosts DNA repair capacity, D, stabilizes AR proteins, or E, silences luminal genes and promotes lineage change. So, as I mentioned earlier, there's a number of different epigenetic uh changes that we, that are relevant for tumor biology. I'm gonna focus here on EZ-H2 since this is the one that again, is probably the best studied in prostate cancer and currently is being targeted as a therapeutic strategy with a number of new agents. So, ECH2 is the enzymatic subunit of the polycomer plusive complex or PRCA2, and it catalyzes the deposition of repressive H3K27 trimethylation marks. Uh, we see that when you look at, uh, later-stage prostate cancers, that there's an enrichment in EZH2 activity with mRNA levels going up as you progress from, uh, benign prostate cancer cases to, uh, sorry, when you progress from benign prostates to prostate cancer cases to cast resistant prostate cancer, and the highest overall expression is seen in those that have evidence of neuroendocrine transformation. Uh, one model by which ECH2 may facilitate this, uh, change in lineage is that NMC can redirect ECH2 activity to target gene promoters and suppress luminal epithelial programs, including those mediated by angio receptor. This in turn would allow the neuroendocrine lineage to emerge in that context. Looking at pre-clinical models, we see that inhibition of ECH2 activity can block trans differentiation, but overall, there's limited in vivo activity when ECH-2 inhibitors are used in neuroendocrine models as shown in the studies on the right here. It's also notable that EZ-H2 has a non-canonical function and whereby it can collaborate directly with the AR transcriptional machinery to drive air signaling by itself, and that's independent of the role that it plays in promoting lineage plasticity. It's also notable that ECH2 activity differs in angioreceptor positive compared to neuroendocrine-positive prostate cancers, and you can see that the ECH2 mark H3K27 trimethylation is different, uh, depending on whether it's an error positive or neuroendocrine-positive case. This leads to silencing of neuroendocrine lineage transcription factors in AR positive prostate cancers, whereas in the neuroendocrine cases, we see that the the uh H3K27 trimethylation marks lead to silencing of luminal genes and those involved in epithelial transcription factors. I wanted to briefly talk a little bit about some of the clinical work that's gone into developing EZH2 inhibitors, and I'm going to focus on Mevrametastat since this is the one furthest in development. It is notable, however, that there's a number of other ECH2 or PR C2 inhibitors that are currently in clinical development. This is the study schematic from a phase 2 expansion portion of a clinical trial testing mevrametastat in combination with enzalutamide versus enzalutamide alone. This study enrolled patients with metastatic castrate resistant prostate cancer who had previously been treated with abiraterone. They were allowed to have received one or fewer prior lines of chemotherapy in any setting, and they must have had progression at time of enrollment per prostate cancer Working Group 3 criteria. All patients were also maintained on androgen deprivation therapy. A total of 81 patients were randomized 1 to 1 between the two treatment arms, and the primary endpoint was radiographic progression-free survival as well as safety, and a number of secondary endpoints were assessed as well to determine the pharmacokinetic effects of the drug and also response rates. To show the baseline characteristics here, and just notable that these are fairly well-matched between the two groups. And that almost 50% of patients on this study had previously been exposed to taxane chemotherapy. The study did show that there was an improved progression-free survival in patients who got the combination of mevrametastat and enzalutamide with a 49% reduction in the risk of progression at any time point. This translated into a median RPFS of 14.3 months for patients getting mevrometastat and enzalutamide versus 6.2 months for patients getting enzalutamide alone. In terms of the response rates, they see radiographic responses occurred in 26% of patients getting the combination, whereas only 14% of patients receiving enzalutamide had a response. The proportion of patients who had a 50% or greater decline in PSA was also higher in patients who received memetastat plus enzalutamide at 34.1%, compared to 15.4% in patients who got enzalutamide monotherapy. In terms of safety, the majority of patients in both arms had a treatment emergent adverse event. These were mostly lower grade, and it's notable that uh very few patients discontinued treatment due to a treatment emergent adverse event. Some of the more common adverse events observed included those that were related to GI. Toxicity such as diarrhea. It's notable that currently, this drug is being tested at a lower dose in combination with food, which has been a, a good strategy in terms of mitigating some of the GI toxicity that was previously observed in this phase two expansion part of this study. I also point out that