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Metastatic Castration-Resistant Prostate Cancer Clinical Trial Landscape

Metastatic castration-resistant prostate cancer has 3 active Phase 3 programs recruiting in 2026 — Merck's opevesostat (CYP11A1 inhibitor), Pfizer's mevrometostat (EZH2 inhibitor), and Novartis's actinium-225 PSMA radioligand. Get daily alerts for protocol changes, new trials, and enrollment updates.

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Active Phase 3 mCRPC Programs (2026)

NCT IDDrug / MechanismSponsorPhaseStatus
NCT06136624 Opevesostat (MK-5684) — CYP11A1 inhibitor vs. NHA Merck Phase 3 Recruiting
NCT06136650 Opevesostat (MK-5684) — CYP11A1 inhibitor vs. NHA (2nd cohort) Merck Phase 3 Recruiting
NCT06629779 Mevrometostat (PF-06821497) — EZH2 inhibitor + enzalutamide Pfizer Phase 3 Recruiting
NCT06780670 AAA817 — actinium-225 PSMA RLT vs. standard of care Novartis Phase 2/3 Recruiting
NCT02257736 Apalutamide + abiraterone vs. placebo + abiraterone Aragon/Janssen Phase 3 Active, not recruiting
NCT03748641 Niraparib + abiraterone (BRCA-mutated mCRPC) Janssen Phase 3 Active, not recruiting

Active Phase 2 Programs

NCT IDDrug / MechanismSponsorStatus
NCT05489211 Dato-DXd (TROP2 ADC) ± anti-cancer agents in mCRPC AstraZeneca Recruiting
NCT06863272 Ifinatamab deruxtecan (I-DXd) — STEAP2 ADC combinations Merck Recruiting
NCT06842498 FG-3246 — PSMA-targeted small molecule in mCRPC Kyntra Bio Recruiting
NCT05658003 177Lu-PSMA-617 vs. ARPI switch in mCRPC Novartis Active, not recruiting
NCT05848011 Lorigerlimab (bispecific PD-1/CTLA-4) + docetaxel in mCRPC MacroGenics Active, not recruiting

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The mCRPC Treatment Landscape in 2026

Metastatic castration-resistant prostate cancer (mCRPC) is defined by disease progression despite castrate levels of testosterone (<50 ng/dL). As of 2026, the approved standard-of-care includes: AR pathway inhibitors (enzalutamide, apalutamide, darolutamide), the CYP17A1 inhibitor abiraterone acetate, taxane chemotherapy (docetaxel, cabazitaxel), lutetium-177 PSMA-617 (Pluvicto) for PSMA-positive mCRPC, radium-223 for bone-metastatic mCRPC, and PARP inhibitors (olaparib, rucaparib) for BRCA-mutated mCRPC.

The key unmet need driving the 2026 clinical trial landscape is resistance to approved therapies — particularly ARPI resistance (most patients progress within 12–18 months on enzalutamide or abiraterone) and the growing post-lutetium PSMA population who have no established treatment options after Pluvicto progression.

The Three Emerging Resistance-Targeting Mechanisms

Key Questions in mCRPC Research (2026)

1. Can CYP11A1 inhibition overcome ARPI resistance?

Abiraterone targets CYP17A1 (one step in androgen synthesis). Enzalutamide blocks the AR directly. Both leave CYP11A1 — the first enzymatic step converting cholesterol to pregnenolone — intact. Opevesostat's mechanism plugs this upstream bypass. Merck's two Phase 3 trials (NCT06136624, NCT06136650) will provide definitive data on whether this translates to a survival benefit in ARPI-pretreated mCRPC.

2. Is alpha-emitting PSMA RLT the next step after Pluvicto?

After lutetium PSMA-617 approval (VISION trial, OS benefit in PSMA-positive mCRPC), the next clinical question is: what happens after progression? Novartis's AAA817 actinium-225 trial directly tests whether alpha-PSMA can provide meaningful benefit in patients who exhausted beta-PSMA. Alpha particles have ~1,000× higher cell-killing efficiency per decay vs. beta particles, but produce more off-target effects if PSMA is expressed in normal tissues. The NEPTUNE Phase 2/3 trial will be closely watched by the nuclear oncology community.

3. Where do ADCs fit in the mCRPC armamentarium?

ADCs have transformed breast cancer and are emerging in prostate. The two active mCRPC ADC programs in 2026 target distinct antigens: Dato-DXd (TROP2, AstraZeneca) which has approvals in breast/lung cancer is being explored in mCRPC; ifinatamab deruxtecan (STEAP2, Merck) specifically targets a prostate-enriched antigen. Neither is approved yet; both are in Phase 1/2. The critical question is whether the TROP2/STEAP2 expression profile in mCRPC is sufficient to drive clinical benefit.

FAQ

Frequently asked questions

What is opevesostat (MK-5684) and why does Merck have two Phase 3 mCRPC trials?
Opevesostat (MK-5684) is a CYP11A1 inhibitor co-developed by Merck and Orion, a novel mechanism that blocks androgen synthesis at the first step of the steroidogenic pathway, upstream of where abiraterone (which targets CYP17A1) acts. By targeting CYP11A1, opevesostat is designed to suppress residual androgen production that can drive resistance to approved androgen receptor pathway inhibitors (ARPIs). Merck is running two parallel Phase 3 trials in metastatic castration-resistant prostate cancer (mCRPC) patients who progressed after an ARPI and taxane-based chemotherapy: OMAHA-003 (MK-5684-003, NCT06136624) and OMAHA-004 (MK-5684-004), both comparing opevesostat to a switch to an alternative ARPI.
What is mevrometostat (PF-06821497) and how does it differ from AR-pathway drugs?
Mevrometostat (PF-06821497) is Pfizer's EZH2 inhibitor, an epigenetic approach to mCRPC that is mechanistically distinct from approved androgen receptor (AR)-targeting therapies. EZH2 (Enhancer of Zeste Homolog 2) is a histone methyltransferase whose activity is upregulated in castration-resistant prostate cancer and that co-regulates AR-driven gene programs. By blocking EZH2, mevrometostat aims to delay or reverse antiandrogen resistance. Pfizer is running two Phase 3 trials in combination with enzalutamide: MEVPRO-1 (NCT06551324), in patients previously treated with abiraterone, and MEVPRO-2 (NCT06629779), in ARPI-naive mCRPC patients. If successful, this would be among the first approved epigenetic agents in prostate cancer.
What is AAA817 (Novartis) and how does it compare to lutetium-PSMA-617 (Pluvicto)?
AAA817 is Novartis's investigational PSMA-targeted actinium-225 radioligand therapy, an alpha-emitting radioligand that differs from lutetium-177 PSMA-617 (Pluvicto) in its radioactive payload. Lutetium-177 emits beta particles (lower energy, longer path length), while actinium-225 emits alpha particles (higher energy, extremely short path length of a few cell diameters), which could offer greater cytotoxicity per decay with less irradiation of surrounding tissue. Novartis's Phase 2/3 trial (NCT06780670) compares AAA817 versus standard of care in mCRPC patients who progressed on lutetium-177 PSMA-617, testing whether alpha-emitting PSMA therapy can overcome resistance to beta-emitting PSMA therapy.
What PARP inhibitor options exist in mCRPC?
PARP inhibitors are established in HRR-mutated (homologous recombination repair) mCRPC. Olaparib (Lynparza), in combination with abiraterone and prednisone, is FDA-approved for BRCA-mutated mCRPC, based on the PROpel trial. Niraparib plus abiraterone (Akeega) is FDA-approved for BRCA-mutated mCRPC (approved August 2023, based on the MAGNITUDE trial), and later also gained an FDA approval for BRCA2-mutated metastatic castration-sensitive prostate cancer. Active trials continue to explore PARP inhibitors in HRR-broader, non-BRCA populations and in novel combinations; the key open question is whether PARP inhibitors add benefit outside BRCA1/2-mutated patients, where Phase 3 results to date have been mixed.
How can I track mCRPC clinical trials?
DataLookout monitors ClinicalTrials.gov daily and delivers email digests of new and updated mCRPC trials filtered by your criteria. Track by drug (opevesostat, mevrometostat, AAA817, olaparib, niraparib), by mechanism (CYP11A1 inhibitor, EZH2 inhibitor, PSMA radioligand, PARP inhibitor), or by biomarker (BRCA, HRR). The free plan includes 1 sponsor + 1 disease watchlist and 1 saved search with email alerts; Starter ($49/month) allows 3 + 3 watchlists and 3 saved searches; Pro ($149/month) is unlimited.

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Related Pages

Live trial data Data as of 2026-08-28, ClinicalTrials.gov

269 active trials, 155 recruiting. Phases: Early Phase 1: 8, Phase 1: 126, Phase 2: 128, Phase 3: 26, Phase 4: 5.

Top sponsorTrials
Novartis Pharmaceuticals10
AstraZeneca9
Bayer6
Pfizer5
Amgen3

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Notable trials Ranked by recent tracked changes, ClinicalTrials.gov data as of 2026-08-28
TrialStatusLatest tracked changeSeen
Dose-Escalation Study of Cabozantinib in Combination With Lutetium-177… NCT05613894RecruitingRecruitment resumed after suspension2026-08-13
A Phase I Clinical Study of HLX3902 in Patients With mCRPC and Other Advanced… NCT07533708RecruitingTrial sites expanded: 0 → 5 locations2026-08-12
Cell Therapy (STEAP1 CART) With Enzalutamide for the Treatment of Patients With… NCT06236139RecruitingPrimary endpoint(s) modified2026-08-12
TmPSMA-02 in mCRPC NCT06046040Active, Not RecruitingEnrollment closed, study ongoing2026-08-11
Cannabidiol for Pain Relief of Patients With End-stage mCRPC NCT07549256RecruitingRecruitment opened2026-08-08

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