FDA Approves Talazoparib Plus Enzalutamide for Genetically Impaired HRR mCRPC

The FDA has approved talazoparib (Talzenna) plus enzalutamide (Xtandi) for use in patients with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR).1

The regulatory decision was based on results from the Phase 3 TALAPRO-2 study (NCT03395197), in which the addition of talazoparib to enzalutamide significantly improved radiographic progression-free survival (rPFS) compared with enzalutamide alone in this population. Median rPFS has not yet been reached (95% CI, 21.9-not estimable) in the investigational arm vs 13.8 months (95% CI, 11.0-16.7) with enzalutamide alone (HR, 0, 45, 95% CI, 0.33-0.61; P < .0001).

Data from an exploratory analysis of BRCA extension mutational status showed the risk ratio for rPFS in those whose tumors harbored BRCA extension mutations (n ​​= 155) was 0.20 (95% CI, 0.11-0.36) in favor of the talazoparib combination. The median rPFS was not estimable compared to 11.0 months (95% CI, 8.3-11.1) in the experimental and control arms, respectively. In those without these mutations, median rPFS was 24.7 months (95% CI, 16.4-NE) and 16.7 months (95% CI, 13.8-27.7), respectively (HR, 0 .72; 95% CI, 0.49-1.07).


The double-blind, placebo-controlled, multicohort study enrolled patients with HRR genetically mutated mCRPC (n = 399). Patients were required to have an ECOG performance status of 0 or 1.2 They also needed to have progressed on prior androgen deprivation therapy. Prior treatment with docetaxel or a CYP17 inhibitor for metastatic castration sensitive disease was permitted.

Researchers prospectively determined mutation status using solid tumor tissue or next-generation sequencing assays. Participants had to have a mutation in at least 1 of the following 12 genes involved in the HRR pathway: ATM, atr, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2OR RAD51C.

Study participants were randomly assigned 1:1 to receive talazoparib at a daily dose of 0.5 mg (n = 200) or placebo (n = 199) plus enzalutamide at a daily dose of 160 mg. Treatment continued until disease progression or intolerable toxicity. Specifically, all patients received a gonadotropin-releasing hormone analogue or had previously undergone bilateral orchidectomy.

A key factor in stratification was prior treatment with a CYP17 inhibitor or docetaxel (yes vs no).

The mean age of study participants was 70 years (range, 41-90) and all were male. The majority were White (68%) and had an ECOG performance status of 0 (62%) at baseline. Additionally, 39% of patients had only bone disease and 15% had visceral disease. In the metastatic castration sensitive setting, 29% had previously received docetaxel and 9% had a CYP17 inhibitor. In this group, the most common mutated HRR gene was BRCA2 (34%), followed by ATM (22%), CDK12 (19%), CHEK2 (18%), e BRCA1 (6%).

rPFS assessed by blinded independent central review by RECIST v1.1 and Prostate Cancer Working Group criteria served as the primary efficacy outcome measure. Overall survival was another key efficacy outcome measure.

The rPFS results were consistent in patients who were and had not been previously exposed to a CYP17 inhibitor or docetaxel. At the time of the rPFS analysis, the OS data were not yet mature; 24% had died by this time.

Of the patients receiving talazoparib, 86% were exposed for at least 6 months, 60% were exposed for at least 12 months, and 18% were exposed for more than 24 months.

Regarding safety, the most common toxicities seen in at least 10% of patients who received the doublet included laboratory abnormalities, 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.

Serious toxicities were experienced by 30% of patients who received the doublet and included anemia (9%) and fractures (3%). Fatal adverse reactions were experienced by 1.5% of patients and this included pneumonia, COVID-19 infection and sepsis.

10% of patients discontinued talazoparib due to toxicity. The most common reasons for discontinuation included anemia (4%), fatigue (1%), bone fractures (1%), ischemic heart disease (1%), and spinal cord compression (1%).

Fifty-eight percent of patients required dose interruptions due to adverse effects and 52% required dose reductions.


  1. FDA approves talazoparib with enzalutamide for metastatic castration-resistant prostate cancer with HRR gene mutation FDA. June 20, 2023. Accessed June 20, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant -prostata
  2. Talzenna (talazoparib). Prescribing information. June 2023. Accessed June 20, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211651s010lbl.pdf

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