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PARP inhibitors in mCRPC
Precision Medicine in Metastatic Castration–Resistant Prostate Cancer: Leveraging PARP Inhibitors for Optimal Outcomes

Released: July 15, 2025

Expiration: January 14, 2026

Neeraj Agarwal
Neeraj Agarwal, MD, FASCO
Karim Fizazi
Karim Fizazi, MD, PhD
Rana R. McKay
Rana R. McKay, MD, FASCO
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Key Takeaways
  • Routine genetic testing is critical for identifying actionable homologous recombination repair gene mutations in all patients with metastatic prostate cancer.
  • Emerging data support expanded use of poly (ADP-ribose) polymerase (PARP) inhibitor combinations beyond traditional BRCA mutations.
  • Anticipated data from early intervention studies could additionally reshape clinical management practices, underscoring the value of precision medicine in prostate cancer care.

The Centrality of Genetic Testing in mCRPC
Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed the care of patients with metastatic castration–resistant prostate cancer (mCRPC), particularly for patients with DNA repair defects or genetic mutations in the homologous-recombination repair (HRR) pathway. It is becoming increasingly clear that genetic testing should be a routine aspect of treating patients with metastatic prostate cancer. Current guidelines from the American Society of Clinical Oncology (ASCO) strongly recommend that every patient diagnosed with metastatic prostate cancer undergo comprehensive genetic testing, which includes both somatic and germline evaluations. Somatic, or tumor, testing can help inform treatment decisions and patient prognosis, and germline testing can inform treatment decisions along with the potential cascade testing of family members for increased cancer risk.

Despite these clear guidelines, implementation remains suboptimal as a result of multifactorial barriers. One major challenge that we face is logistical since many practices do not have in-house testing capabilities. Testing services are provided by external services, requiring coordination that can seem cumbersome in busy clinical settings. Another significant barrier is patient and healthcare professional (HCP) awareness. Patients might not fully understand the implications for their treatment and for their family members, and HCPs may be uncertain about interpreting test results or integrating them into clinical decisions.

We know that approximately 25% of patients with mCRPC harbor HRR mutations, such as BRCA1, BRCA2, ATM, PALB2, and CDK12. Identifying these mutations can expand treatment options for patients which in turn can improve clinical outcomes. testing accessibility, coupled with patient and HCP education, is paramount for enhancing care.

Improving Clinical Adoption of Genetic Testing
In clinical practice, there are some practical ways to integrate genetic testing more efficiently. Fresh tumor biopsies remain ideal, but when not feasible, circulating tumor DNA (ctDNA) liquid biopsies have become a reliable alternative. Of importance, ctDNA testing should ideally occur prior to initiating a new treatment, as tumor DNA levels may rapidly decline following treatment initiation which can impact testing results.

Second, simplifying the testing process is crucial. Whether through internal institutional protocols or clearly defined external pathways, reducing complexity encourages broader adoption by HCPs across various specialties.

Considerations for PARP Inhibitors in Clinical Practice
The evidence for prioritizing the use of PARP inhibitors in mCRPC continues to expand rapidly. The PROfound and TRITON3 trials provided compelling evidence supporting the efficacy of the single-agent PARP inhibitors olaparib and rucaparib in patients with specific HRR gene mutations, particularly BRCA2. The FDA has approved olaparib for patients with mCRPC and deleterious HRR mutations (including BRCA1/2, ATM, CDK12) following progression on enzalutamide or abiraterone, and rucaparib for patients with germline or somatic BRCA1/2 mutations after prior AR-targeted therapy and taxane-based chemotherapy. The European Medicines Agency has approved olaparib for BRCA-mutated mCRPC postAR therapy, whereas rucaparib holds conditional approval specifically for BRCA-mutated mCRPC. These approvals highlight the critical role of HRR genetic testing, with BRCA1/2 mutations remaining the most reliable predictive biomarkers for PARP inhibitor benefit.

Several landmark trials—PROpel, MAGNITUDE, and TALAPRO-2—provided crucial insights into combination strategies with PARP inhibitors and androgen receptor pathway inhibitors. The PROpel trial demonstrated improved radiographic progression-free survival (rPFS) with olaparib plus abiraterone acetate/prednisone (AAP) vs placebo plus AAP across HRR mutation-positive groups, especially BRCA-mutated patients. The final prespecified OS (42 months vs 35 months) analysis further supported the clinical benefit of the combination. Of note, there was a larger percentage of patients with reduction in the prostate-specific antigen level of ≥50% with the CDK12-mutation (a historically challenging subset) who received olaparib plus AAP vs placebo plus AAP (83% vs 62%, respectively) but there was no difference between treatment arms in patients with ATM mutations.

The MAGNITUDE trial compared niraparib plus AAP vs placebo plus APP and reinforced the effectiveness of the combination strategy in BRCA-positive patients with mCRPC and HRR alterations, showing significant improvements in rPFS and a trend toward longer overall survival (OS) benefit. At ASCO 2025, data from phase III AMPLITUDE trial with niraparib and AAP vs placebo plus AAP for patients with metastatic castration–sensitive prostate cancer and HRR alterations showed significant improvement in rPFS and time to symptomatic progression with the addition of niraparib to AAP. Similar to some of the other trials, the most benefit was observed in patients with BRCA mutations, whereas those with other HRR mutations (including CHEK2, CDK12, FANCA, PALB2) had less clear efficacy benefits. These new data suggests that there may be a potential benefit to moving PARP inhibitor combination therapy to earlier in the disease, particularly for patients with BRCA mutations.

The TALAPRO-2 trial assessed talazoparib plus enzalutamide vs placebo plus enzalutamide in patients with newly diagnosed mCRPC, which also provided compelling insights. The trial met its primary endpoint of improved median rPFS for patients with HRR deficiency and showed substantial benefits across various HRR mutations. Final results also showed improved median OS with the addition of talazoparib in patients with HRR deficiency and a trend toward OS benefit in HRR–proficient tumors. Also, at ASCO 2025, an exploratory analysis of TALAPRO-2 suggested efficacy benefit for patients with various HRR deficiencies, including BRCA2, BRCA1, PALB2, CDK12, and ATM mutations. Patients with CDK12  and ATM-mutated mCRPC are groups that have historically responded poorly to PARP inhibition alone. However, this analysis demonstrated significantly improved rPFS (30 months vs 18 months) and OS (45 months vs 39 months) in ATM-mutated patients treated with talazoparib-enzalutamide combination compared with enzalutamide alone. Similarly, patients with CDK12 mutations also showed meaningful clinical benefit. In this cohort, the combination therapy achieved a median rPFS (19 months vs 14 months) and OS (36 months vs 23 months).

These emerging data suggest a shift toward expanded options for PARP inhibitors, with both monotherapy and combination approaches now available. However, more data is needed to fully understand the implications of various non-BRCA HRR deficiencies on the efficacy of PARP inhibitor–based therapy, particularly in subsets like ATM and CDK12 mutations.

The Clinical Value of a Personalized Approach
Given these insights, personalization of therapy based on comprehensive genetic profiling has become a cornerstone of modern mCRPC management. Patients with BRCA2 deletions in particular clearly benefit from these approaches and warrant prioritized access to PARP inhibitor combinations. Moreover, emerging data support expanding this approach to additional HRR mutations, including patients with BRCA1, ATM, and CDK12 mutations, provided that combination therapy is an option.

Enhancing Patient and Family Communication
Ultimately, the integration of genetic testing and targeted therapies like PARP inhibitors demands a patient-centered approach. Shared decision-making ensures that patients fully appreciate the rationale for testing and potential treatment benefits for themselves and their families. Explaining genetic implications not only personalizes care but empowers patients and their families, fostering greater adherence and satisfaction with care plans.

Understanding the familial implications of germline mutations significantly affects patient decisions, compliance, and overall satisfaction. By clearly explaining the potential genetic risks to family members, especially for cancers such as ovarian and breast cancer, we provide patients with deeper motivation and context for accepting and adhering to testing and treatment protocols.

Identifying actionable mutations and selecting the most effective therapy combinations for individual patients significantly improves outcomes. Our clinical practices must evolve accordingly, harnessing these powerful strategies for maximal patient benefit.

Your Thoughts?
How will the recent findings on PARP inhibitor combinations impact your clinical practice? What strategies do you find most effective for incorporating genetic testing into your decision-making process?

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In your clinical practice, how often do you test for HRR alterations in your patients with metastatic prostate cancer?

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