Oncology Learning NetworkPARP Inhibitors as Treatment Options for Monotherapy and Combination Therapy in HRRm or BRCAm Prostate Cancer

In this video, Tanya Dorff, MD, Division Chief of the Genitourinary Disease Program at City of Hope in Duarte, California, discusses PARP inhibitors, particularly olaparib, for treatment of metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair mutations (HRRm) or BRCA mutations (BRCAm). The content examines two key registrational trials: PROfound for olaparib monotherapy and PROpel for combination therapy with abiraterone.

⚕️Key Clinical Considerations⚕️

• Up to 25% of mCRPC patients have homologous recombination repair gene mutations (HRRm), making them potential candidates for PARP inhibitor therapy which triggers cell death in HRR-deficient cancer cells.
• The PROfound trial demonstrated 66% lower risk of disease progression or death in HRRm patients receiving olaparib versus control (enzalutamide/abiraterone), with 78% risk reduction specifically in BRCA-mutated mCRPC.
• In PROpel, first-line olaparib plus abiraterone showed 34% decreased risk of disease progression in all patients, with notably stronger benefit (76% risk reduction) in the BRCA-mutation subgroup.
• Safety profile across both trials showed anemia as the most common serious adverse reaction, with other common reactions including nausea, fatigue, and decreases in blood cell counts.
• FDA approved olaparib as monotherapy for HRRm mCRPC after progression on enzalutamide/abiraterone, and in combination with abiraterone for BRCA-mutated mCRPC.

🎯 Clinical Practice Impact 🎯

• Patient Selection: Genomic testing is critical to identify HRRm and particularly BRCA mutations, as these subgroups showed the most pronounced benefits in clinical trials. For patients with BRCA mutations, consider early implementation of PARP inhibitor therapy given the aggressive nature of this disease variant and strong efficacy signals.
• Treatment Sequencing: For HRRm patients who progressed on AR pathway inhibitors (enzalutamide/abiraterone), olaparib monotherapy is supported by PROfound data. For BRCA-mutated patients who have not received an AR pathway inhibitor, combination of olaparib with abiraterone is supported by PROpel data.
• Monitoring Requirements: Regular monitoring for anemia, neutropenia, and other hematologic abnormalities is essential, as decreases in hemoglobin, lymphocytes, leukocytes, and neutrophil count were common laboratory findings.

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