PARP inhibitors as first-line therapy for men with mCRPC and BRCA1 or BRCA2 variants

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

In the intent-to-treat (ITT) population, the median radiographic PFS was 24.8 months in the olaparib group and 16.6 months in the placebo group (HR, 0.66; 95% CI, 0.54–0.81).

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

In an exploratory analysis of the subset of patients with BRCA-altered disease (n = 85, 11% of the ITT population), the observed median radiographic PFS was not reached in the olaparib group and was 8 months in the placebo group (HRradiographic PFS,0.24; 95% CI, 0.12–0.45; and HROS, 0.30; 95% CI, 0.74–1.14).[82,83][Level of evidence B1]

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

Data from the exploratory analysis suggested that the radiographic PFS benefit in the ITT population was primarily attributable to BRCA-altered status. Therefore, the FDA has only approved this drug for patients with BRCA-altered disease.

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

OS, a key secondary end point, was not significantly different between treatment groups at the final prespecified analysis. Median OS was 42.1 months in the olaparib group and 36.5 months in the placebo group (HR, 0.81; 95% CI, 0.67–1.00; P = .054).[84]

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

Grade 3 or higher adverse events occurred in 41% of patients in the olaparib group and 34% of patients in the placebo group. Anemia was the most common grade 3 or higher adverse event (occurring in 3% of patients in the olaparib group and 16% of patients in the placebo group). Of the patients with anemia who required at least one blood transfusion, 18% were in the olaparib group and 4% were in the placebo group.

The phase III, randomized, double-blinded, PROpel trial (NCT03732820) studied the PARP inhibitor olaparib with abiraterone and prednisone (or prednisolone) as first-line treatment in patients with mCRPC. In the trial, 796 patients were randomly assigned in a 1:1 ratio to receive either (1) olaparib (300 mg twice daily) with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily) or (2) placebo with abiraterone (1,000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Prior systemic therapy for mCRPC was excluded, but prior docetaxel for metastatic hormone-sensitive prostate cancer was allowed. The presence of variants in tumor homologous recombination repair genes (including BRCA) was determined retrospectively using both tumor tissue and circulating tumor DNA (ctDNA). The study design did not prospectively evaluate variants in homologous recombination repair genes or BRCA, nor did it stratify randomization by biomarker status. The primary end point was investigator-assessed radiographic PFS.[82]

FACT-P questionnaire scores were similar between treatment groups, indicating no significant detriment to patients' health-related QOL with the addition of olaparib with abiraterone.