2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Prostate Cancer

The Emerging Role of PARP Inhibitors in Prostate Cancer: A Narrative Review - Beyond the Abstract

The clinical development of PARP inhibitors (PARPi) in prostate cancer has been driven by the recognition that alterations in DNA damage repair (DDR) genes — particularly homologous recombination repair (HRR) defects — define a biologically distinct and therapeutically targetable subset of disease. Approximately 25–30% of men with advanced prostate cancer harbor DDR mutations, with BRCA2 being the most frequent, followed by ATM, CDK12, and PALB2.


1. mCRPC Monotherapy

Early evidence from TOPARP-A/B showed that olaparib elicited responses in 88% of DDR-mutated tumors vs 6% in DDR–. The benefit was greatest in BRCA1/2 (median PFS 8.3 months), more modest in ATM (5.8 months), and limited in CDK12 (2.9 months).
Subsequent phase II (GALAHAD, TRITON-2, TALAPRO-1) and phase III studies (PROfound, TRITON-3) confirmed the gene-specific benefit:

  • GALAHAD (Niraparib): ORR 34%, rPFS 8.1 months, and OS 13.0 months in BRCA, vs ORR 10%, rPFS 3.7 months, and OS 9.6 months in non-BRCA.
  • TRITON-2 (Rucaparib): ORR 46%, PFS 10.7 months, and OS 17.2 months in BRCA, with remarkable efficacy in PALB2 (ORR 100%, rPFS 13.6 months), but negligible activity in ATM/CHEK2/CDK12.
  • TALAPRO-1 (Talazoparib): ORR 46.2%, PFS 11.2 months in BRCA2, but only 6.7% and 3.5 months in ATM.
  • PROfound (Olaparib): rPFS (7.4 vs 3.6 months; HR 0.34) and OS (19.1 vs 14.7 months; HR 0.69) in BRCA1/2 or ATM, with post-hoc analyses confirming the strongest benefit in BRCA1/2 (rPFS HR 0.22; OS HR 0.63).
  • TRITON-3 (Rucaparib): In pre-chemotherapy mCRPC, rucaparib prolonged rPFS in BRCA1/2, but at ASCO-GU 2025 update, final OS did not reach significance (23.2 vs 21.2 months; HR 0.91). No benefit was seen in ATM (HR 1.21).
2. mCRPC Combinations

PARPi+ARPI combinations exploit AR–DDR crosstalk, inducing “BRCAness” in HRR-proficient tumors.

  • PROpel (Olaparib+Abiraterone): rPFS 24.8 vs 16.6 months (HR 0.66) in ITT. BRCA1/2 derived the greatest benefit (HR 0.23). OS trended longer (42.1 vs 34.7 months, HR 0.81), significant in HRR+ (HR 0.66) and BRCA (HR 0.29).
  • MAGNITUDE (Niraparib+Abiraterone): HRR– closed early. In HRR+, rPFS 16.7 vs 13.7 months (HR 0.76); in BRCA1/2, 19.5 vs 10.9 months (HR 0.55). OS not improved.
  • TALAPRO-2 (Talazoparib+Enzalutamide): In the unselected all-comers population, rPFS was not reached versus 21.9 months (HR 0.63). Among patients with HRR+ tumors, rPFS was significantly prolonged at 30.7 months compared to 12.3 months (HR 0.47). Final overall survival (OS) data, presented at ASCO-GU 2025, demonstrated an 8.8-month improvement (45.1 vs 31.1 months; HR 0.62), establishing this regimen as a new standard of care for HRR+ mCRPC. At ASCO 2025, an exploratory gene subgroup analysis revealed pronounced benefit in BRCA2-mutated patients (ORR 86.4%, rPFS HR 0.25, OS HR 0.47), with additional gains observed in PALB2 and CDK12, and modest activity in CHEK2.
  • BRCAAway (Abiraterone+Olaparib): phase II trial further emphasized the genomic rationale: in HRR-mutated mCRPC, abiraterone+olaparib yielded a median PFS of 39 months, compared with 14 months for olaparib and 8.4 months for abiraterone alone (HR 0.28 vs AAP; HR 0.32 vs olaparib).
  • CASPAR (Enzalutamide+Rucaparib, ongoing): will clarify outcomes, including in non-BRCA disease.
3. mHSPC

Moving earlier in the disease, PARPi is under active investigation in metastatic hormone-sensitive prostate cancer (mHSPC).

  • AMPLITUDE (Niraparib+abiraterone): The first interim analysis, reported at ASCO 2025, demonstrated a significant improvement with the combination in rPFS (NR vs 29.5 months; HR 0.63; p=0.0001), with an immature positive OS trend (HR 0.79). BRCA1/2 patients derived marked benefit (rPFS HR 0.52; OS HR 0.75).
  •  TALAPRO-3 (Talazoparib+enzalutamide): Talazoparib+enzalutamide vs enzalutamide in HRR-mutated mHSPC is ongoing
  • EvoPAR-PR01 (Saruparib+hormonal therapy): under study in mHSPC regardless of HRR status.
These results suggest that early PARPi+ARPI integration may replicate mCRPC successes and redefine standards in BRCA-driven mHSPC.

4. New Frontiers

Neoadjuvant Setting

  • FAST-PC (Fuzuloparib+Abiraterone): In high-risk localized PC, achieved 46% combined pCR/MRD and 53% 2-year bPFS, with faster PSA declines in BRCA2/HRR-mutated patients.
  • CaNCaP03 (Olaparib±Degarelix): Showed PSA decline and PARP inhibition in pre-op samples.
  • GUNS (Niraparib) & NePtune (Olaparib in BRCA1/2): evaluating pathologic response and MRD clearance.
Adjuvant Setting

  • NCT04037254 (Niraparib+RT+ADT) reported a 30% PSA decline, rising to 33% in BRCA1/2. Adjuvant studies remain early-phase but promising.
  • Biochemical Recurrence (BCR)
  • ROAR (Rucaparib): PSA-PFS 35.3 months in high-risk HRR+ BCR, though the study closed early.
  • NCT03047135 (Olaparib): HRR+ patients had PSA50 in 48%, including 100% of BRCA2.
Future Directions

  • Combination strategies: PARPi with immunotherapy (C3NIRA: Niraparib+Cetrelimab improved OS 24.3 vs 10.2 months, p=0.01), or with radioligands (LuPARP, COMRADE, NiraRad).
  • Functional biomarkers: Needed beyond genomics to stratify ATM/CDK12/CHEK2.
  • Treatment sequencing: Determining optimal timing of monotherapy vs combination will be key to maximizing benefit and preventing resistance.
Conclusion

The benefit of PARP inhibition in prostate cancer is gene- and stage-specific.

  • mCRPC monotherapy: Durable efficacy in BRCA1/2 and PALB2, limited in ATM, CHEK2, CDK12.
  • mCRPC combinations: Extend survival across broader HRR+ populations, with TALAPRO-2 and PROpel confirming OS benefit, strongest in BRCA2.
  • mHSPC (AMPLITUDE): Supports earlier use, especially in BRCA-driven disease.
  • New frontiers (neoadjuvant, adjuvant, BCR): Open the door to PARPi in curative-intent settings, where HRR mutations may guide intensified therapy.
Written by: Lorenzo Lobianco, MD, Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy

References:

  1. Lobianco L, Calvanese G, D'Ausilio D, Rossetti S, Cecere SC, Ventriglia J, Pisano C, Tambaro R, Napoli MD, Passarelli A, Roma C, Luca A, Sepe F, Cozzolino S, Perri E, Lamia MR, Moccia C, Pignata S. The emerging role of PARP inhibitors in prostate cancer: A narrative review. Cancer Treat Rev. 2025 Jul 25;140:103000. doi: 10.1016/j.ctrv.2025.103000. Epub ahead of print. PMID: 40848312.
Read the Abstract