On June 20, the U.S. Food and Drug Administration (FDA) approved talazoparib (Talzenna) with enzalutamide for homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer.
TALAPRO-2
Efficacy was evaluated in TALAPRO-2 (ClinicalTrials.gov identifier NCT03395197), a randomized, double-blind, placebo-controlled, multicohort trial enrolling 399 patients with HRR gene–mutated metastatic castration-resistant prostate cancer. Patients were randomly assigned 1:1 to receive enzalutamide at 160 mg daily plus either talazoparib at 0.5 mg or placebo daily.
Patients were required to have undergone a prior orchiectomy and, if not performed, have received gonadotropin-releasing hormone (GnRH) analogs. Patients who had received prior systemic therapy for metastatic castration-resistant prostate cancer were excluded; however, prior treatment with CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer was permitted. Random assignment was stratified by previous treatment with a CYP17 inhibitor or docetaxel. HRR genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) were assessed prospectively using tumor tissue and/or circulating tumor DNA–based next-generation sequencing assays.
The major efficacy outcome measure was radiographic progression–free survival per Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone, assessed by blinded independent central review. A statistically significant improvement in radiographic progression–free survival for talazoparib with enzalutamide compared to placebo with enzalutamide was observed in the HRR gene–mutated population, with a median that was not reached vs 13.8 months (hazard ratio [HR] = 0.45, 95% confidence interval [CI] = 0.33–0.61, P < .0001). In an exploratory analysis by BRCA mutation status, the hazard ratio for radiographic progression–free survival in patients with BRCA-mutated metastatic castration-resistant prostate cancer (n = 155) was 0.20 (95% CI = 0.11–0.36) and, in patients with non–BRCA mutated, HRR gene–mutated metastatic castration-resistant prostate cancer, was 0.72 (95% CI = 0.49–1.07).
The most common adverse reactions occurring in ≥ 10% of patients treated with the combination regimen, including laboratory abnormalities, were decreased hemoglobin, decreased neutrophils, decreased lymphocytes, fatigue, decreased platelets, decreased calcium, nausea, decreased appetite, decreased sodium, decreased phosphate, fractures, decreased magnesium, dizziness, increased bilirubin, decreased potassium, and dysgeusia. Among all patients with metastatic castration-resistant prostate cancer treated with talazoparib plus enzalutamide in TALAPRO-2 (n = 511), 39% required a blood transfusion, including 22% who required multiple transfusions, and two patients were diagnosed with myelodysplastic syndrome/acute myeloid leukemia.
The recommended talazoparib dose is 0.5 mg taken orally once daily in combination with enzalutamide until disease progression or unacceptable toxicity. The recommended enzalutamide dose is 160 mg taken orally once daily. Patients receiving talazoparib and enzalutamide should also receive a GnRH analog concurrently or should have undergone bilateral orchiectomy.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review.
