Talzenna Combo Approved for HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer

The Food and Drug Administration (FDA) has approved Talzenna^® (talazoparib), in combination with enzalutamide, for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

The approval was based on data from the TALAPRO-2 study (ClinicalTrials.gov Identifier: NCT03395197), a randomized, double-blind, placebo-controlled, multi-cohort trial in which 399 patients with HRR gene-mutated (HRRm) mCRPC were randomly assigned to receive talazoparib 0.5mg plus enzalutamide 160mg daily (n=200) or placebo plus enzalutamide 160mg daily (n=199) until unacceptable toxicity or progression. The primary endpoint of the study was radiographic progression free survival (rPFS); overall survival (OS) was a secondary outcome measure.

Findings showed a statistically significant improvement in rPFS in patients treated with talazoparib plus enzalutamide compared with placebo plus enzalutamide (median rPFS, not evaluable [21.9, not evaluable] vs 13.8 months [11.0-16.7], respectively; hazard ratio 0.45, [95% CI, 0.33-0.61]; P <.0001). These results were consistent in patients who received or did not receive a prior CYP17 inhibitor or docetaxel. Overall survival data were not mature at the time of analysis; final OS data are expected in 2024.

In an exploratory rPFS subgroup analysis, the HRs were reported to be 0.20 (95% CI, 0.11-0.36) for patients with BRCA-mutated (BRCAm) mCRPC (n=155) and 0.72 (0.49-1.07) for patients with non-BRCAm HRR gene-mutated mCRPC (n=244).

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive 1 line of therapy,” said Neeraj Agarwal, MD, FASCO, Professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, and global lead investigator for TALAPRO-2. “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. 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 most common adverse reactions reported with the combination 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.

Talzenna, a poly (ADP-ribose) polymerase (PARP) inhibitor, is supplied as a capsule in 0.1mg, 0.25mg, 0.35mg, 0.5mg, 0.75mg, and 1mg strengths. Patients receiving Talzenna and enzalutamide should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy.