Prostate Cancer Clinical Trials 2026: PARP Inhibitors, PSMA Therapy & mCRPC

Prostate cancer has seen two transformative advances in the past five years: PSMA-targeted radioligand therapy that delivers targeted radiation directly to tumor cells expressing a prostate-specific membrane antigen, and PARP inhibitors that exploit DNA repair deficiencies in patients with BRCA1/2 and other homologous recombination mutations. Neither approach was in routine clinical use a decade ago. In 2026, the question has moved beyond "do these work?" to "where should they go in the treatment sequence?" — trials are now testing whether earlier use improves outcomes and whether combinations can delay or overcome resistance. For patients, the molecular complexity of this trial landscape is considerable, but the payoff is a set of treatment options that is meaningfully better than what existed previously.

PSMA-Targeted Radioligand Therapy: From Approval to Sequencing Questions

Lutetium-177 PSMA-617 (Pluvicto, Novartis) received FDA approval in March 2022 for PSMA-positive mCRPC following prior ARPI therapy and taxane-based chemotherapy. The VISION trial (NCT03511664) showed improved radiographic PFS (HR 0.40, p<0.001) and improved OS (HR 0.62, p<0.001) versus best supportive care in heavily pre-treated patients. The drug works by binding PSMA — a membrane protein highly expressed on prostate cancer cells — and delivering Lu-177, a beta-emitting radioisotope, directly to the tumor cell, sparing surrounding normal tissue.

What makes the 2026 trial landscape interesting is that the approval question has been answered. The current questions are about sequence and combination. Active trials include:

• Earlier use in hormone-sensitive disease: The PSMAfore trial (NCT04689828) tested Pluvicto vs. ARPI switch in ARPI-pretreated mCRPC, and data is maturing. The PSMAaddition trial is testing Pluvicto in metastatic hormone-sensitive prostate cancer — before castration resistance develops.
• Actinium-225 PSMA (alpha emitter): Ac-225 delivers alpha radiation, which has shorter range but higher local energy deposition than the beta emission of Lu-177. Phase 2 trials show response rates in the 70–80% range in patients who have already progressed on Lu-177 PSMA — the alpha emitter appears to work even after beta failure. Phase 3 trials are being designed.
• PSMA-directed CAR-T: Phase 1 trials at MSKCC and other centers are testing PSMA-targeted CAR-T cells in mCRPC. Very early, very small numbers, but represents the extension of the CAR-T approach to a solid tumor with a well-validated surface target.
• Combinations with PARP inhibitors: PSMA therapy causes DNA damage; PARP inhibitors block DNA repair. The combination is mechanistically rational for BRCA-mutated tumors. Phase 1/2 combination trials are running.

PSMA PET scan — using tracers such as 68Ga-PSMA-11 (Illuccix) or 18F-DCFPyL (Pylarify) — is required to confirm adequate PSMA expression before eligibility for most PSMA-targeted therapy trials. If you have metastatic prostate cancer and have not had a PSMA PET, this is a critical conversation to have with your oncologist before evaluating trial eligibility.

PARP Inhibitors: The Approved Options and What Comes Next

The rationale for PARP inhibitors in prostate cancer is synthetic lethality: cells with homologous recombination repair (HRR) deficiencies — caused by mutations in BRCA1, BRCA2, ATM, CDK12, CHEK2, and other HRR genes — depend on PARP for alternative DNA repair. Block PARP, and the cell cannot repair double-strand DNA breaks, leading to death. In normal cells with functional HRR, backup repair pathways compensate. The selectivity is elegant.

Olaparib (Lynparza) received FDA approval for BRCA1/2-mutated mCRPC based on the PROfound trial (NCT02987543), which showed a 34% ORR and median rPFS of 7.4 months vs. 3.6 months for ARPI switch. Niraparib plus abiraterone (Akeega) was approved in 2023 for BRCA1/2-mutated mCRPC after the MAGNITUDE trial. Approximately 25% of mCRPC patients have HRR gene mutations, making HRR testing the first actionable biomarker evaluation after the diagnosis of castration resistance.

• Broader HRR populations: PROfound showed benefit primarily in BRCA1/2; the data for ATM and CDK12 mutations was less clear. Multiple trials are evaluating PARP inhibitors specifically in non-BRCA HRR-mutated mCRPC to characterize which HRR alterations beyond BRCA predict response.
• Earlier disease stages: The PROpel trial evaluated olaparib + abiraterone vs. abiraterone alone in unselected first-line mCRPC regardless of HRR status — showing rPFS benefit in the ITT population. Post-hoc analyses showed the benefit was concentrated in BRCA-mutated patients. Trials are now designing for frontline BRCA-selected populations.
• Combinations with immunotherapy: CDK12-mutated tumors have high focal tandem duplications that generate neoantigens — making them potentially immunogenic. Phase 2 trials combining PARP inhibitors with PD-1 checkpoint blockade in CDK12-mutated mCRPC are ongoing, attempting to generate an immune response in a tumor type otherwise resistant to immunotherapy.

AR Pathway Resistance and What Comes After ARPIs

Enzalutamide (Xtandi) and abiraterone (Zytiga/Yonsa) are first-generation ARPIs that transformed mCRPC treatment a decade ago. Enzalutamide in the PREVAIL trial reduced risk of death by 29% vs. placebo; abiraterone in COU-AA-301 extended OS by a median of 4.6 months in post-docetaxel patients. These drugs remain foundational. But resistance inevitably develops, and the mechanisms of resistance — principally AR splice variant 7 (AR-V7), AR gene amplification, and ARPI-cross resistant point mutations — are now reasonably well characterized and targetable.

• AR-V7 and resistance: AR-V7 is a constitutively active AR splice variant that lacks the ligand-binding domain — making it resistant to enzalutamide and abiraterone, which work by blocking ligand binding. AR-V7-positive patients rarely respond to ARPI switch. Testing for AR-V7 in circulating tumor cells (Oncotype DX AR-V7) or circulating tumor DNA is available clinically and guides decisions about switching to a different mechanism.
• PSMA × CD3 bispecific antibodies: T cell engaging bispecifics that bind PSMA on prostate cancer cells and CD3 on T cells simultaneously, redirecting cytotoxic T cells to kill tumor cells without prior sensitization. Tarlatamab for SCLC validated the bispecific T cell engager mechanism in solid tumors; PSMA-targeted bispecifics (xaluritamig, pasotuxizumab, AMG 160) are in Phase 1/2 for mCRPC with promising early response data.
• AKT inhibitors for PTEN-deleted mCRPC: PTEN deletion occurs in ~40% of mCRPC, activating the PI3K/AKT pathway. The IPATential150 trial showed capivasertib + abiraterone improved rPFS in PTEN-deleted patients (HR 0.56 vs. 0.92 in PTEN-normal patients). Further trials combining AKT inhibitors with ARPIs in PTEN-selected populations are active.

The Biomarker Workup Every mCRPC Patient Should Have Done

The practical problem in prostate cancer trial navigation in 2026 is that most trials require specific biomarker data that may not have been collected during standard oncology workup. Getting the right tests done before contacting trial sites avoids delays at pre-screening:

• Germline testing (blood): BRCA1, BRCA2, and full HRR panel. This is heritable testing — BRCA2 in particular has implications for family members. NCCN guidelines recommend germline testing for all metastatic prostate cancer patients.
• Somatic tumor profiling (tissue biopsy or liquid biopsy): HRR mutations, CDK12, MSI-H/dMMR, AR amplification/mutations. Somatic and germline BRCA mutations are different — a tumor can have somatic BRCA inactivation without germline carrier status, and both are actionable.
• PSMA PET: Required for PSMA-targeted therapy eligibility. Expression is scored on PSMA PET — high PSMA expression (score ≥2 on multiple lesions) is the typical threshold for trial eligibility.
• AR-V7 testing: From circulating tumor cells or ctDNA. Guides decisions about ARPI switch vs. non-AR mechanism trials in patients progressing on first-line ARPI.
• Prior treatment documentation: Most mCRPC trials require specific prior treatment sequences — ARPI-naive vs. ARPI-pretreated, taxane-pretreated vs. taxane-naive. Having a clear treatment timeline with dates and responses accelerates pre-screening substantially.

Key Takeaways

• Germline BRCA2 mutation is the most predictive single biomarker for mCRPC treatment decisions — olaparib and niraparib/abiraterone are FDA-approved for BRCA-mutated mCRPC. Get tested if you haven't, regardless of family history.
• PSMA PET imaging has transformed staging and therapeutic targeting. Lu-177 PSMA (Pluvicto) has Phase 3 OS data in mCRPC and is now FDA-approved — trials testing earlier use and Ac-225 alpha emitter approaches are active.
• AR-V7 positivity predicts resistance to enzalutamide and abiraterone. Patients with AR-V7 detected in circulating tumor cells should prioritize trials with non-AR mechanisms — PSMA therapy, PARP inhibitors, or bispecific antibodies.
• Comprehensive somatic tumor profiling and germline testing are complementary, not redundant — both should be completed before evaluating trial eligibility for mCRPC.
• GU oncology programs at NCI-designated Cancer Centers have the broadest prostate cancer trial portfolios. Coordinating biomarker workup before the consultation visit is the most efficient approach.

Finding Prostate Cancer Trials in 2026

Search ClinicalMetric for "prostate cancer" or "castration-resistant prostate cancer" filtered by Phase and Recruiting status. NCI-designated Cancer Centers with dedicated Genitourinary (GU) oncology programs have the broadest portfolio of prostate trials. PARP inhibitor trials require confirmed HRR mutation documentation — ensure germline and somatic profiling are completed before contacting trial sites to avoid delays in pre-screening. The ZERO Prostate Cancer patient advocacy organization maintains a trial navigation program and connects patients to GU oncology specialists.