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mCRPC Synergy Series: Overcoming Resistance and Optimizing Pathways | Part 2: Sequencing After ARPI

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 2 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 (Current Module)

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.

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:

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.

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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.

The learning objective is to formulate and implement evidence-based sequencing strategies for patients progressing on a first-line ADT plus ARPI agent, incorporating genomic biomarkers where available, and imaging biomarkers where available into individualized treatment planning. So let's begin with a poll question. We have a 65-year-old man diagnosed previously with de novo, low volume metastatic hormone sensitive prostate cancer, Gleason score 4 + 4 equals 8. Who develops progression to metastatic castration resistant disease 14 months after receiving initial therapy with ADT and anzalutamide doublets. His germline and somatic genetic testing is negative. A PSMA PET scan obtained at the time of metastatic castration resistant progression shows 3 bone lesions, each with SUV max values between 4 and 8. And one of those bone lesions has begun to cause pain. What is his best next systemic therapy? Uh, please take a look at the answers and cast your votes. So let's begin with mapping out the treatment landscape for prostate cancer. This is a slide that I've used many times in my lectures, starting with the localized disease state on the left. Uh, in the middle, we have the castration sensitive or hormone sensitive state, which often starts as a biochemical recurrence and then can become a metastatic hormone sensitive state. And then on the far right-hand side, we can see the advanced stage of the disease, which is the castration resistance stage. Either without metastases, the so-called M0 CRPC or the M1 CRPC state, and each of these boxes are shown in gray are the therapeutic agents which have been approved for each of those states. Now we're going to focus in on the um first line metastatic CRPC setting here uh for the remainder of the talk. I also want to point out that very recently, the prostate Cancer Working Group 4 guidelines have been published. And one of the changes in these guidelines is that we are simplifying the clinical states model. Uh, as you can see here, this slide looks a bit more, uh, simple and streamlined than the previous one. the boxes in blue are all of the, uh, states that we used to call, uh, castration sensitive or castration naive. Um, because many patients do not like the term, uh, castration, uh, we have adopted a new terminology, androgen pathway modulation sensitive or naive. And then what was previously known as castration resistant prostate cancer in yellow, uh, we are proposing that this should now be called androgen pathway modulation resistant. Uh, a bit of a mouthful, but over time we hope that, uh, these new terminologies will be adopted and again. Um, the states here, uh, also have to do with whether there is non-metastatic disease or metastatic disease identified on conventional or, uh, molecular imaging. And then on the, on the far right, instead of referring to first line, second line, third line, uh, MCRPC, uh, what we are now proposing, uh, as I mentioned before, is the androgen pathway modulation resistant terminology. And there instead of lines of therapy, we are simply recommending, uh, documenting uh the specific type and number of prior systemic therapy received. Now, if one looks at the NCCM guidelines, uh, the most current version, uh, the majority of, of this session will deal with the uh patient who has developed metastatic uh castration resistant prostate cancer who has previously received ADT plus an ARPI agent. And the box in the middle, which is circled in uh blue, uh, shows the NCCN. Uh, options for that patient, as you can see, docetaxel chemotherapy is category one. in the context of, uh, HRR or BRCA mutations, there are a number of PARP inhibitor options, and then, uh, there are also options relating to PSMA positive disease, uh, with Letitia PSMA as well as, uh, cabazitaxel carboplatin combination for aggressive variant prostate cancer. This is a helpful table that reminds us of the uh indications for the PAARP inhibitor monotherapies in this setting, Olarib or Rcarib, as well as the PARP inhibitor plus ARPI combinations. And uh just to remind the audience here that the level one evidence in this setting is uh for Olarib as a monotherapy and rocarib as a monotherapy. The evidence is a bit weaker for the three combinations, and the reason is, uh, those three trials, uh, the Propel, the telepromp 2, and the magnitude study. Largely enrolled patients who had not previously received an ARPI prior to becoming castration resistant. Um, the, the genetic biomarkers are slightly different for these agents. Uh, the elaborate monotherapy has the broadest panel of genes, uh, incorporating 14 HRR genes, while a recarib, for example, is FDA approved only for a germlinerurosomatic BRCA1 or BRCA2 mutations. I just wanted to highlight the Triton 3 study. This was a phase 3 trial of recarib in the first-line uh metastatic castration resistant setting in patients who had received one and only one prior ARPI agent. Uh, they were randomized to, uh, recarib or the physician choice, and this incorporated either abiraterone or enzalutamide switch. Or importantly, uh, docetaxel chemotherapy was also part of the trial here. Uh, the genetic subset that was included were patients with BRCA1 and 2, as well as ATM, a germline or somatic genetic mutations. The trial met its primary endpoint. If you look at the left part of the slide, you can see that recarib improves progression-free survival PFS compared to the control group. And of course you have to remember the control group was a mix of ARPI switch and docetaxel chemotherapy. But what I found very interesting is on the right-hand side, we are now splitting that control group according to the two different components. So the top shows the recap rib curve against the patients that received docetaxel in the control arm. And the bottom shows recarib against patients receiving an ARPI switch. And while we can clearly see that the magnitude of benefit is greater, uh, when the control arm is the RP switch, we still do see a clinically significant and statistically significant improvement over dose of Taxel. Uh, in this setting, and to me that was quite profound because it implies that especially for patients with BRCA1 and BRCA2 mutations who reach the first line MCRPC state having received one prior RP, for those patients, docetaxel is probably not the most important next therapy for them, and a PARP inhibitor such as recarib or perhaps even ollarib might be a better choice. Next, of course, we do need to discuss uh radioligand therapies including Letitia PSMA 617. Uh, these are agents targeting the prostate-specific membrane antigen receptor, and a ligand in this case bound to a beta emitter, lutein 177 is delivered into the PSMA positive expressing cells. The first line MCRPC study of this agent was called PSMA 4. Once again, these were patients with metastatic CRPC who had received one and only one prior ARPI agent. They were randomized after a PSMA, uh, PET scan. The PSMA PET scan had to be positive, uh, for, uh, PSMA radio tracer avid metastatic disease. And then they were randomized a 1 to 1 ratio to receive the TM PSMA 617 once every 6 weeks for 6 cycles or the RP switch. And this is a radiographic progression pre survival point. A very important consideration here was that the trial had a planned crossover. In patients who were first randomized to the RP switch and in fact,