The US Food and Drug Administration (FDA) has approved talazoparib (Talzenna) in combination with enzalutamide (Xtandi) for adults with metastatic androgen pathway modulation-naïve or -sensitive prostate cancer with homologous recombination repair (HRR) gene mutations, expanding the combination's use to an earlier treatment setting.
Previously approved for HRR-mutated metastatic castration-resistant prostate cancer, the combination is now available before castration resistance develops. Eligible patients must have an HRR gene mutation identified by an FDA-authorized test. The previously approved FoundationOneCDx and FoundationOne Liquid CDx companion diagnostics can identify eligible patients.
The decision was supported by TALAPRO-3, a randomized, double-blind, placebo-controlled phase 3 trial involving 599 patients with HRR-mutated metastatic androgen pathway modulation-naïve or -sensitive prostate cancer. Patients were randomly assigned 1:1 to receive daily talazoparib plus enzalutamide or placebo plus enzalutamide. All participants continued androgen deprivation therapy.
HRR mutation status was determined prospectively using next-generation sequencing of tumor tissue or circulating tumor DNA. Eligible alterations included BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.
The primary end point was investigator-assessed radiographic progression-free survival, based on RECIST version 1.1 and Prostate Cancer Working Group 3 criteria for bone lesions.
Talazoparib plus enzalutamide reduced the risk of radiographic progression or death by 52% compared with placebo plus enzalutamide. Median radiographic progression-free survival was not reached in the combination group versus 45.8 months in the control group (hazard ratio, 0.48). Overall survival data remained immature at the time of analysis.
Hematologic toxicity was a significant safety consideration. According to Pfizer, grade 3 or higher anemia occurred in 51% of patients receiving talazoparib plus enzalutamide compared with 3% receiving placebo plus enzalutamide. Anemia led to permanent talazoparib discontinuation in 5% of treated patients. Other commonly reported adverse events included fatigue, decreased neutrophil count, and asthenia.
Prescribing information includes warnings for myelodysplastic syndrome or acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. Complete blood counts should be monitored before treatment and monthly thereafter.
The recommended talazoparib dose is 0.5 mg orally once daily with enzalutamide until disease progression or unacceptable toxicity. Patients must also receive a gonadotropin-releasing hormone analog or have undergone bilateral orchiectomy. Talazoparib dose reductions are recommended for patients with moderate or severe renal impairment.
The application received Priority Review and was evaluated through the FDA's Project Orbis initiative, with concurrent reviews involving regulators in Australia and Canada.
