PARP inhibitors as first-line therapy for men with mCRPC and variants in homologous recombination repair genes

The combination of a PARP inhibitor, talazoparib, with enzalutamide was tested in the phase III, double-blind, randomized, multicohort TALAPRO-2 study (NCT03395197) as first-line therapy in men with mCRPC. The trial enrolled two cohorts in which patients were prospectively assessed for variants in homologous recombination repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11, NBN, PALB2, and RAD51C) in tumor tissue and/or ctDNA. Patients were randomly assigned in a 1:1 ratio to receive either talazoparib (0.5 mg once daily) or placebo with enzalutamide (160 mg once daily). Prior systemic therapy for mCRPC was excluded. Prior docetaxel and abiraterone for metastatic castration-sensitive prostate cancer was permitted. Results from combined cohorts of the homologous recombination repair gene-altered population included 399 patients. The primary end point was radiographic PFS.[85,86]

The combination of a PARP inhibitor, talazoparib, with enzalutamide was tested in the phase III, double-blind, randomized, multicohort TALAPRO-2 study (NCT03395197) as first-line therapy in men with mCRPC. The trial enrolled two cohorts in which patients were prospectively assessed for variants in homologous recombination repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11, NBN, PALB2, and RAD51C) in tumor tissue and/or ctDNA. Patients were randomly assigned in a 1:1 ratio to receive either talazoparib (0.5 mg once daily) or placebo with enzalutamide (160 mg once daily). Prior systemic therapy for mCRPC was excluded. Prior docetaxel and abiraterone for metastatic castration-sensitive prostate cancer was permitted. Results from combined cohorts of the homologous recombination repair gene-altered population included 399 patients. The primary end point was radiographic PFS.[85,86]

The median radiographic PFS was not reached in the talazoparib-with-enzalutamide group and was 13.8 months in the placebo-with-enzalutamide group (HR, 0.45; 95% CI, 0.33–0.61; P < .0001). In patients with BRCA-altered mCRPC (n = 155) the HRradiographic PFS was 0.20 (95% CI, 0.11–0.36). The median follow-up for radiographic PFS was 17.5 months in the talazoparib group and 16.8 months in the placebo group.[85,86][Level of evidence B1]

The combination of a PARP inhibitor, talazoparib, with enzalutamide was tested in the phase III, double-blind, randomized, multicohort TALAPRO-2 study (NCT03395197) as first-line therapy in men with mCRPC. The trial enrolled two cohorts in which patients were prospectively assessed for variants in homologous recombination repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11, NBN, PALB2, and RAD51C) in tumor tissue and/or ctDNA. Patients were randomly assigned in a 1:1 ratio to receive either talazoparib (0.5 mg once daily) or placebo with enzalutamide (160 mg once daily). Prior systemic therapy for mCRPC was excluded. Prior docetaxel and abiraterone for metastatic castration-sensitive prostate cancer was permitted. Results from combined cohorts of the homologous recombination repair gene-altered population included 399 patients. The primary end point was radiographic PFS.[85,86]

Grade 3 or higher adverse events occurred in 68% of patients in the talazoparib-with-enzalutamide group and 40% of patients in the placebo-with-enzalutamide group.

The combination of a PARP inhibitor, talazoparib, with enzalutamide was tested in the phase III, double-blind, randomized, multicohort TALAPRO-2 study (NCT03395197) as first-line therapy in men with mCRPC. The trial enrolled two cohorts in which patients were prospectively assessed for variants in homologous recombination repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11, NBN, PALB2, and RAD51C) in tumor tissue and/or ctDNA. Patients were randomly assigned in a 1:1 ratio to receive either talazoparib (0.5 mg once daily) or placebo with enzalutamide (160 mg once daily). Prior systemic therapy for mCRPC was excluded. Prior docetaxel and abiraterone for metastatic castration-sensitive prostate cancer was permitted. Results from combined cohorts of the homologous recombination repair gene-altered population included 399 patients. The primary end point was radiographic PFS.[85,86]

The most common grade 3 or higher adverse event was anemia (41% in the talazoparib group and 5% in the placebo group). Thirty-nine percent of patients in the talazoparib group required a blood transfusion.

The combination of a PARP inhibitor, talazoparib, with enzalutamide was tested in the phase III, double-blind, randomized, multicohort TALAPRO-2 study (NCT03395197) as first-line therapy in men with mCRPC. The trial enrolled two cohorts in which patients were prospectively assessed for variants in homologous recombination repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11, NBN, PALB2, and RAD51C) in tumor tissue and/or ctDNA. Patients were randomly assigned in a 1:1 ratio to receive either talazoparib (0.5 mg once daily) or placebo with enzalutamide (160 mg once daily). Prior systemic therapy for mCRPC was excluded. Prior docetaxel and abiraterone for metastatic castration-sensitive prostate cancer was permitted. Results from combined cohorts of the homologous recombination repair gene-altered population included 399 patients. The primary end point was radiographic PFS.[85,86]

Talazoparib with enzalutamide significantly prolonged time to definitive, clinically meaningful deterioration versus placebo with enzalutamide (HR, 0.69; 95% CI, 0.49–0.97; P = .032).