On 20 June 2023, the US Food and Drug Administration (FDA) approved talazoparib (Talzenna, Pfizer, Inc.) with enzalutamide for homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
Full prescribing information for Talzenna is available here.
Efficacy was evaluated in TALAPRO-2 (NCT03395197), a randomised, double-blind, placebo-controlled, multi-cohort study enroling 399 patients with HRR gene-mutated mCRPC. Patients were randomised (1:1) to receive enzalutamide 160 mg daily plus either talazoparib 0.5 mg or placebo daily. Patients were required to have a prior orchiectomy and, if not performed, received gonadotropin-releasing hormone (GnRH) analogues. Patients with prior systemic treatment for mCRPC were excluded; however, prior CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer was permitted. Randomisation 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 tumour tissue and/or circulating tumour DNA-based next generation sequencing assays.
The major efficacy outcome measure was radiographic progression-free survival (rPFS) per RECIST 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 rPFS for talazoparib with enzalutamide compared to placebo with enzalutamide was observed in the HRR gene-mutated population with a median that was not reached versus 13.8 months (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.33, 0.61; p < 0.0001). In an exploratory analysis by BRCA mutation status, HR for rPFS in 155 patients with BRCA-mutated mCRPC was 0.20 (95% CI 0.11, 0.36) and 0.72 (0.49, 1.07) in patients with non-BRCA-mutated, HRR gene-mutated mCRPC.
The most common adverse reactions (≥ 10%), including laboratory abnormalities, were decreased haemoglobin, 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 mCRPC treated with talazoparib with enzalutamide on TALAPRO-2 (n = 511), 39% required a blood transfusion, including 22% who required multiple transfusions, and 2 patients were diagnosed with myelodysplastic syndrome/acute myeloid leukaemia.
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 analogue concurrently or should have had 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.
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