FDA Grants Approval to Talazoparib Plus Enzalutamide for HRR-Gene Altered mCRPC


On the heels of an ASCO presentation of data from the phase 3 TALAPRO-2 trial, the FDA has granted approval to the study combination for the treatment of a metastatic castration-resistant prostate cancer subgroup.

  • Talazoparib is the first PARP inhibitor to be granted approval with an approved standard-of-care therapy, enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration resistant prostate cancer (mCRPC).

  • In addition to the United States approval, a marketing authorization application has been accepted for review by the European Medicines Agency.

  • The agent has approval in over 70 countries for the treatment of BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.

The FDA has granted approval to the combination of talazoparib (Talzenna) plus enzalutamide (Xtandi) for the treatment of patients with HRR gene–mutated mCRPC.1

Findings from the phase 3 TALAPRO-2 trial (NCT03395197) support the approval. According to data recently presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, the combination achieved statistically significant and clinically meaning progression free survival (PFS) improvement as a first-line therapy for patients with mCRPC that have HRR gene-altered disease.2

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive one line of therapy. Therefore, new first-line treatment options are needed to reduce the risk of disease progression or death. For patients with mCRPC harboring HRR genetic alterations, outcomes are even worse,” said Neeraj Agarwal, MD, FASCO, professor and presidential endowed chair of Cancer Research at Huntsman Cancer Institute, University of Utah, in a press release.1 “The FDA’s approval of the talazoparib and enzalutamide combination is based on the findings from the pivotal TALAPRO-2 study, which demonstrated statistically significant and clinically meaningful reductions in the risk of progression or death among HRR gene-mutated tumors in patients with metastatic castration-resistant prostate cancer. It represents a treatment option deserving of excitement and attention.”

The primary endpoint of radiographic PFS (rPFS) with a 55% reduced risk of progression of death in patients on the combination arm (n = 200) was achieved in the TALAPRO-2 study, despite median rPFS was not being reached (NR) in the talazoparib arm (95% CI, 21.9-NR) compared with 13.8 months (95% CI, 11.0-16.7) in the placebo arm (HR, 0.45; 95% CI, 0.33-0.61, P < 0.0001). Further, the combination showed in a 37% lower risk of rPFS in the talazoparib plus enzalutamide arm compared with the placebo plus enzalutamide arm (HR, 0.63; 95% CI 0.51–0.78; P < 0.0001).2

In the HRR gene-altered subgroup, there was also an rPFS benefit demonstrated with talazoparib plus enzalutamide (HR, 0.44; 95% CI, 0.32-0.60, P < 0.0001), and this benefit was extended to the BRCA-mutated population (HR, 0.20; 95% CI, 0.11-0.36, P < 0.0001) as well as the non-BRCA population (HR, 0.68; 95% CI, 0.46-1.02; P = 0.060).

Additional results showed that talzoparib with first-line enzalutamide also prolonged the time to PSA progression for these mCRPC patients, resulting in an approximately 40% reduction of risk between both arms. A median of 28.6 months (95% CI, 26.7-NR) time to PSA progression in the treatment arm was seen compared with 11.1 months (95% CI, 9.3-13.9) in the placebo and enzalutamide arm (HR, 0.41; 95% CI, 0.30-0.57, P < 0.0001).

Time to cytotoxic chemotherapy was improved with the combination at 38 events vs 65 in the placebo arm (HR, 0.46; 95% CI, 0.31-0.79, P = 0.0001). Moreover, there was a median PFS2 of 36.4 months (95 CI, 364.4-NR) and 28.1 months (95% CI, 24.5-NR), respectively (HR, 0.57; 95% CI, 0.39-0.85, P = 0.0045).

The combination arm had an objective response rate (ORR) of 67.1, which included complete responses in 38.4% of patients and stable disease rate of 26% was observed, while 5.6% of remaining patients on the combination arm had progressive disease. Comparatively, the ORR was 40% in the placebo arm with 18.5% of those responses being complete, 32.3% had stable disease and 20% had progressive disease.

There were no new safety signals observed with talazoparib when combined with enzalutamide in the study. Investigators reported grade 3-4 treatment emergent adverse effects (TEAEs) in 66.2% of patients in the combination therapy vs 37.2% of those in the placebo and enzalutamide treatment. Of those treated with the combination, 67.2% of patients had a dose interruption of talazoparib due to an AE compared with 19.6% of those on the placebo arm and 55.6% of patients in the combination arm had to dose reduce their talazoparib. Overall, treatment discontinuation rates were low in both arms.

“Pfizer has a legacy of bringing medicines to patients with genitourinary cancers and helping improve outcomes for patients suffering from advanced prostate cancer,” said Angela Hwang, chief commercial officer, president, Global Biopharmaceuticals Business, Pfizer, in the press release.1 “As a global standard of care, Xtandi has shown efficacy in three types of prostate cancer, and the addition of Talzenna demonstrated significant improvements in delaying or preventing radiographic progression-free survival or death in patients with this type of advanced prostate cancer. With today’s FDA approval of Talzenna plus Xtandi, we are proud to be able to offer this potentially practice-changing treatment to patients and add to their options in managing this aggressive disease.”


1. Pfizer’s TALZENNA® in combination with XTANDI® receives U.S. FDA approval. News release. Pfizer. June 20, 2023. Accessed June 20, 2023. https://tinyurl.com/y9vahdu3

2. Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2023;5004(suppl 16). doi: 10.1200/JCO.2023.41.16_suppl.5004

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