On June 20, 2023, the U.S. Food and Drug Administration (FDA) approved talazoparib (Talzenna®) with enzalutamide for homologous recombination repair (HRR) gene–variant metastatic, castration-resistant prostate cancer (mCRPC).

FDA Approves Talazoparib With Enzalutamide for HRR Gene–Variant Metastatic Castration-Resistant Prostate Cancer

Efficacy was evaluated in TALAPRO-2 (NCT03395197), a randomized, double-blind, placebo-controlled, multicohort trial of 399 patients with HRR gene–variant mCRPC who were randomized 1:1 to receive daily enzalutamide 160 mg plus either talazoparib 0.5 mg or placebo. Patients were required to have prior orchiectomy or gonadotropin-releasing hormone (GnRH) analog therapy. Those who received prior systemic therapy for mCRPC were excluded; however, prior CYP17 inhibitors or docetaxel for (mCSPC) was permitted. Randomization was stratified by previous treatment with a CYP17 inhibitor or docetaxel. HRR genes (i.e., ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) were assessed prospectively using tumor tissue or circulating tumor 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-variant population with a median that was not reached versus 13.8 months (HR = 0.45; 95% CI = 0.33, 0.61; p < 0.0001). In an exploratory analysis by BRCA variant (BRCAm) status, the hazard ratio for rPFS was 0.20 (95% CI = 0.11, 0.36) in patients with BRCAm mCRPC (n = 155) and 0.72 (0.49, 1.07) in patients with non-BRCAm HRR gene-variant mCRPC.

The most common adverse reactions reported in at least 10% of patients treated with talazoparib with enzalutamide, including laboratory abnormalities, were increased bilirubin, decreased hemoglobin, decreased neutrophils, decreased lymphocytes, fatigue, decreased platelets, decreased calcium, nausea, decreased appetite, decreased sodium, decreased phosphate, fractures, decreased magnesium, decreased potassium, dizziness, and dysgeusia. Among all patients with mCRPC treated with talazoparib with enzalutamide in the trial (n = 511), 39% required a blood transfusion, including 22% who required multiple transfusions, and two patients were diagnosed with myelodysplastic syndrome or acute myeloid leukemia.

The recommended talazoparib dose is 0.5 mg taken orally once daily in combination with enzalutamide until patients experience disease progression or unacceptable toxicity, and the recommended enzalutamide dose is 160 mg taken orally once daily. Patients taking talazoparib and enzalutamide should also receive a GnRH analog concurrently or have had bilateral orchiectomy.

View the full prescribing information for talazoparib.

The review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

The application was granted priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.