PARP inhibitors show unequivocal benefit in mCRPC patients with BRCA1/2 mutations, with potential for earlier treatment sequencing, while lutetium-177 PSMA has gained FDA approval for expanded use before chemotherapy in PSMA-positive patients. These advances represent a shift toward precision oncology with biomarker-driven treatment selection in advanced prostate cancer.
Drug Profile & Regulatory Milestones
- Lutetium Lu 177 vipivotide tetraxetan (Pluvicto): PSMA-targeted radioligand therapy with March 28, 2025 FDA expanded indication for PSMA-positive mCRPC patients post-AR pathway inhibitor therapy where delaying chemotherapy is appropriate
- Original approval: March 2022 for post-AR inhibitor and post-taxane therapy
- Niraparib (Zejula): PARP inhibitor showing benefit in combination with ADT and abiraterone in mCSPC patients with DNA repair mutations
- Companion diagnostics: Gallium Ga 68 gozetotide (Locametz) required for PSMA expression assessment
Key Clinical Evidence & Findings
- PSMAfore Trial (NCT04689828): rPFS 9.3 months vs 5.6 months with lutetium-177 PSMA vs AR pathway inhibitor switch (HR 0.41, P<0.0001)
- PEACE-3 Trial (NCT02194842): Radium-223 plus enzalutamide showed unexpected benefit in bone-dominant mCRPC when incorporating bone-protective agents
- ASCO 2024 niraparib data: Confirmed benefit in mCSPC when combined with ADT and abiraterone in DNA repair mutation patients
- Safety profile: 36% grade ≥3 AEs with lutetium-177 PSMA vs 48% in control arm
Biomarker-Driven Treatment Strategy
- DNA repair mutations (particularly BRCA1/2) serve as robust biomarkers for PARP inhibitor benefit across disease stages
- PSMA expression via PET imaging essential for radioligand therapy patient selection
- Bone-dominant disease identifies candidates for radium-223 combination therapy
- Movement toward earlier use of targeted therapies in biomarker-selected populations
Clinical Practice Implications
- Radioligand therapy established as permanent component of prostate cancer treatment armamentarium
- PARP inhibitors may move earlier in treatment course for patients with DNA repair mutations
- Precision oncology approach enables treatment selection based on tumor biology rather than traditional sequencing
- Triplet regimens with ADT, ARPI, and targeted agents showing promise in castration-sensitive setting
Treatment Sequencing Evolution
- Pre-chemotherapy radioligand therapy now available for appropriate PSMA-positive patients
- Earlier PARP inhibition being evaluated in hormone-sensitive disease
- Bone-protective agents enable safer radium-223 combinations
- Biomarker testing becoming essential for optimal treatment selection
Evidence Quality & Limitations
- PSMAfore trial: No statistically significant OS difference (24.5 vs 23.1 months) with 60% crossover rate
- Expert perspective based on clinical experience and recent trial interpretations
- PEACE-3 results represent unexpected positive finding after ERA-223 failure
- Long-term safety data still emerging for combination approaches
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