Interdisciplinary GU Cancer Forum 2025: Future Directions of mCRPC

(UroToday.com) The 2025 Interdisciplinary Genitourinary Cancer Forum featured a metastatic castration resistant prostate cancer (mCRCP) session and a presentation by Dr. Andrew Hahn discussing future directions of mCRPC. Dr. Hahn started his presentation by noting that we are currently in the golden era for targeting cell surface proteins, with the following targets and mechanisms of action of targeted therapies:

Recently, there has been an explosion of novel radioligand therapies for mCRPC, based on the success of PSMA PET imaging and ¹⁷⁷Lu-PSMA-617 radioligand therapy.^1,2 Dr. Hahn notes that there are two strategies for novel radioligand therapies:

Targeting PSMA with alpha particles or improving beta particles
Targeting novel proteins with established beta and alpha particles

Recently, an alpha emitter, Ac-PSMA I&T, produced PSA50 response of 50%, including those who progressed on ¹⁷⁷Lu-PSMA-617, which is now being assessed in larger trials. Antibody drug conjugates targeting PSMA and STEAP1 had limited activity from 2016 to 2021, but novel antibody drug conjugates are targeting new cell surface proteins and using advances in antibody drug conjugate development. An example of a novel cell surface target is B7-H3 which is overexpressed in prostate cancer and may play a role in the immune system. The B7-H3 DX-d antibody drug conjugate produced some activity in a phase 1/2 trial of mCRPC and is now being developed by Merck in a phase III trial:

Dr. Hahn notes that many CRPC tumors remain addicted to the androgen receptor post-androgen receptor pathway inhibitor treatment, but novel approaches to targeting androgen signaling are needed:

Currently, there are three androgen receptor PROTAC or ligand-directed degraders:

ARV-110 (bavdegalutamide)
ARV-766
BMS-986365

In a phase 1 multicenter trial assessing BMS-986365, patients were enrolled who had progressed on ADT, one or more androgen receptor pathway inhibitors, and taxane chemotherapy.³ There were 27 patients enrolled in the dose escalation portion of the trial, and 68 patients enrolled in the expansion cohort. In the expansion cohort, the median number of prior therapies was 4 (range: 2-11). Across the expansion cohort’s three highest doses (400-900 mg twice daily, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg. The median radiographic progression free survival was 6.3 months (95% CI 5.3-12.6), including 8.3 months (95% CI 3.8-16.6 months) at 900 mg. Radiographic progression free survival was longer in patients without versus with prior chemotherapy: 16.5 months (95% CI 5.5 -not evaluable) versus 5.5 months (95% CI 2.7-8.3), respectively.

Efficacy was also observed in patients with mCRPC with androgen receptor ligand binding domain wild type or with androgen receptor ligand binding domain mutations:

Currently, the rechARge phase 3 trial is enrolling 960 patients, randomizing patients 1:1:1 to two different doses of BMS-986365 or a control arm of investigator’s choice of either docetaxel + prednisone/prednisolone or a secondary androgen receptor pathway inhibitor:

Next, Dr. Hahn emphasized that abiraterone acetate inhibits CYP17A1 and improves overall survival across advanced prostate cancer. A new therapy, opevesostat (ODM-208), inhibits the first step of steroidogenesis, targeting CYP11A1. CYPIDES was the first-in-human phase 1 (3 + 3 design) and phase 2 study,⁴ administering ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing ADT to adults with previously treated mCRPC, regardless of androgen receptor gene ligand-binding domain mutations (phase 1) and with activating androgen receptor ligand-binding domain mutations (phase 2). Overall, there were 92 patients that received one or more doses of ODM-208: 47 in phase 1 (42.6% with an activating androgen receptor ligand-binding domain mutation) and 45 in phase 2. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n = 17, 36.2%; necessitating ODM-208 discontinuation in one patient). Adrenal insufficiency occurred in six patients (13.3%) at 5 mg twice a day in phase 2. A PSA50 response occurred in 14 of 19 (73.7%) patients with an activating androgen receptor ligand-binding domain mutation, and 2 of 23 (8.7%) patients with androgen receptor wild type in phase 1, and in 24 of 45 (53.3%) patients with an activating androgen receptor ligand-binding domain mutation in phase 2:

Currently, OMAHA1 and OMAHA2a are two phase 3 trials that are further assessing ODM-208.

Finally, Dr. Hahn discussed EZH2, which was noted in the early 2000s to be overexpressed in mCRPC. In 2010, it was noted that upregulation of EZH2 plays a role in lineage plasticity, and in the 2020’s multiple EZH2 inhibitor trials were initiated. Mevrometostat is an EZH2 inhibitor with the following mechanism of action:

At ASCO GU 2025, results of a randomized dose-expansion study evaluating the combination of mevrometostat + enzalutamide in mCRPC patients were reported. This trial included mCRPC patients who had received prior abiraterone and ≤1 chemotherapy regimen in any setting and had evidence of disease progression per modified PCWG3 criteria. Eligible patients (n = 81) were randomized 1:1 to mevrometostat 1,250 mg orally twice daily on an empty stomach + enzalutamide 160 mg orally once daily (n = 41) versus enzalutamide 160 mg orally once daily (n = 40). The primary endpoints were radiographic progression free survival per investigator assessment and safety. The trial design for this trial is as follows:

The combination of mevrometostat + enzalutamide was associated with a 49% relative reduction in the rate of progression or death, corresponding to an ~8 month improvement in median radiographic progression free survival (HR 0.51, 90% CI 0.28–0.95):

Dr. Hahn concluded his presentation discussing future directions of mCRPC with the following take home points:

There are many novel therapies in development to treat men with mCRPC
Novel radioligand therapies targeting new cell surface proteins or utilizing alternative radioisotopes are in late-stage development
New ways to target the androgen receptor are being developed in mCRPC and are likely to move into mHSPC soon

Presented by: Andrew Hahn, MD Anderson Cancer Center, Houston, TX

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the Interdisciplinary Genitourinary Cancer Forum 2025, between June 19 – 22, 2025 in St. Petersburg, Florida, United States

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