FDA Approves Talazoparib Plus Enzalutamide for HRR Gene–Altered mCRPC

FDA

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

The regulatory decision was based on findings from the phase 3 TALAPRO-2 trial (NCT03395197), in which the addition of talazoparib to enzalutamide significantly improved radiographic progression-free survival (rPFS) over enzalutamide alone in this population. The median rPFS was not yet reached (95% CI, 21.9-not evaluable) in the investigative 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 mutational status showed that the hazard ratio for rPFS in those whose tumors harbored BRCA mutations (n = 155) was 0.20 (95% CI, 0.11-0.36) in favor of the talazoparib combination. The median rPFS was not evaluable vs 11.0 months (95% CI, 8.3-11.1) in the investigative and control arms, respectively. In those without these mutations, the 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).

TALAPRO-2

The double-blind, placebo-controlled, multicohort trial enrolled patients with HRR gene–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 previous androgen deprivation therapy. Previous treatment with docetaxel or a CYP17 inhibitor for metastatic castration-sensitive disease was allowed.

Investigators prospectively determined mutation status by utilizing solid tumor tissue or next-generation sequencing assays. Participants needed 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, PALB2, or 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 progressive disease or intolerable toxicity. Notably, all patients were given a gonadotropin-releasing hormone analog or previously underwent bilateral orchiectomy.

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

The median 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. Moreover, 39% of patients had bone-only 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%), and BRCA1 (6%).

Blinded independent central review–assessed rPFS by RECIST v1.1 criteria and Prostate Cancer Working Group criteria served as the major efficacy outcome measure. Overall survival represented another key efficacy outcome measure.

The rPFS results proved to be consistent in patients who were and were not 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 at this time point.

Eighty-six percent of patients who received talazoparib were exposed to the drug 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 experienced in at least 10% of patients who received the doublet included 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.

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

Ten percent of patients discontinued talazoparib due to toxicities. The most common reasons for discontinuation comprised anemia (4%), fatigue (1%), bone fracture (1%), ischemic heart disease (1%), and spinal cord compression (1%).

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

WATCH: Neeraj Agarwal, MD, of Huntsman Cancer Institute, University of Utah, discusses the significance of the FDA approval of talazoparib plus enzalutamide in patients with mCRPC harboring HRR gene alterations.

References

1. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastaic castration-resistant prostate cancer. 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-prostate
2. Talzenna (talazoparib). Prescribing information. June 2023. Accessed June 20, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211651s010lbl.pdf