Talazoparib regimen improves outcomes among subset of men with metastatic prostate cancer
Key takeaways:
- Talazoparib plus enzalutamide reduced the risk for disease progression or death by 55% compared with enzalutamide alone.
- Grade 3 or grade 4 events occurred more frequently in the combination therapy group.
CHICAGO — Adding talazoparib to enzalutamide reduced the risk for disease progression or death by 55% in certain men with metastatic castration-resistant prostate cancer, results of the randomized phase 3 TALAPRO-2 trial showed.
A cohort analysis of the study presented at ASCO Annual Meeting revealed the combination of talazoparib (Talzenna, Pfizer) plus enzalutamide (Xtandi; Astellas, Pfizer) as first-line therapy also delayed deterioration in global health status and quality-of-life measurements among men harboring homologous recombination repair (HRR) gene alterations.
“Talazoparib in combination with enzalutamide, if approved [by the FDA], has the potential to become a first-line treatment option for patients with metastatic castration-resistant prostate cancer and HRR gene alterations,” Karim Fizazi, MD, PhD, medical oncologist at Institut Gustave Roussy and professor of oncology at University of Paris-Saclay, said during a presentation.
Background
Enzalutamide — an androgen receptor inhibitor — is currently a standard-of-care option for men with metastatic castration-resistant prostate cancer.
Results of TALAPRO-1 showed the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib as monotherapy was safe and conferred durable antitumor activity among men with metastatic castration-resistant prostate cancer who harbored HRR gene alterations.
“When combining these two agents, we expected additional antitumor activity,” Fizazi said. “Preclinical data suggest there may be synergy.”
Methodology
The randomized, double-blind, placebo-controlled TALAPRO-2 study investigated whether the combination of talazoparib and enzalutamide provided clinically superior PFS compared with enzulatamide alone as first-line therapy for men with metastatic castration-resistant prostate cancer.
Investigators prospectively assessed study participants for several HHR gene alterations, including BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A and CDK12, using either blood- or tissue-based assays.
Fizazi and colleagues presented data on study enrollees with mildly symptomatic or asymptomatic metastatic castration-resistant prostate cancer and HHR gene alterations from cohort 1 (n = 169) and cohort 2 (n = 230) of the trial.
Researchers randomly assigned 200 men (median age, 70 years; range 41-90) to first-line therapy with 0.5 mg talazoparib plus 160 mg enzalutamide daily. The remaining 199 study participants (median age, 71 years; range, 44-90) received placebo plus enzalutamide 160 mg daily.
Radiographic PFS assessed by blinded independent committee review served as the study’s primary endpoint. Secondary endpoints included objective response rate, safety and patient-reported outcomes.
Median follow-up for radiographic PFS was 17.5 months for those who received talazoparib plus enzalutamide and 16.8 months for those who received enzalutamide only.
Key findings
Results showed talazoparib plus enzalutamide significantly extended median radiographic PFS compared with enzalutamide plus placebo (13.8 months vs. not yet reached; HR = 0.45; 95% CI, 0.33-0.61).
Subgroup analysis of radiographic PFS showed a consistent treatment effect in favor of talazoparib plus enzalutamide, notably for the 155 men who harbored BRCA alterations (HR = 0.2; 95% CI, 0.11-0.36).
OS data had not yet matured as of the first interim analysis but showed a trend favoring talazoparib plus enzalutamide compared with enzalutamide plus placebo (not yet reached vs. 33.7 months; HR = 0.69, 95% CI, 0.46-1.03).
Compared with monotherapy, combination therapy with talazoparib plus enzalutamide significantly prolonged median time to PSA progression among study participants with HHR alterations (28.6 vs. 11.1 months; HR = 0.41, 95% CI, 0.3 to 0.57).
Investigators reported an ORR of 67.1% among combination therapy recipients compared with 40% for men who received enzalutamide only (P = .0015). Combination therapy resulted in a 38.4% completer response rate compared with 18.5% among those who received enzalutamide only.
Researchers noted a stable disease rate of 26% in the combination therapy group vs. 32.3% among those who received enzalutamide only. This result, coupled with the higher complete response rate among combination therapy recipients, suggested a synergistic treatment effect with the combination.
No treatment-related deaths occurred during the study.
Twenty men (10%) in the combination therapy group discontinued therapy due to treatment-related adverse events compared with 14 (7%) in the enzalutamide group.
The combination of talazoparib and enzalutamide significantly extended onset of clinically meaningful deterioration in global health status and quality of life when compared with enzalutamide alone (median, 27.1 months vs. 19.3 months; HR = 0.69 95% CI, 0.49-0.97).
Most patients in both treatment groups reported treatment-related adverse events. However, serious grade 3 or grade 4 events occurred more frequently in the talazoparib-enzalutamide group (66.2% vs. 37.2%).
Clinical implications
Not only did the results show superior antitumor activity with talazoparib plus enzalutamide, patient-reported outcomes suggested the novel regimen “preserves quality of life significantly longer” than enzalutamide alone, according to Fizazi.
“Based on these results, I firmly believe that the combination of talazoparib plus enzalutamide should become a standard of care for patients with the combination of metastatic castration-resistant prostate cancer and HRR gene alterations, especially those with BRCA alterations,” he said.
Collapse
Fizazi K, et al. Abstract 5004. Presented at: ASCO Annual Meeting; June 2-6, 2022; Chicago.