Talazoparib/Enzalutamide Combination Prolongs Health Status and Quality of Life in mCRPC

Two prostate cancer cells in the final stage of cell division: ©PRB ARTS - stock.adobe.com

The combination of talazoparib (Talzenna) and enzalutamide (Xtandi) significantly delayed definitive deterioration in global health status and quality of life (GHS/QoL) for patients with metastatic castration-resistant prostate cancer (mCRPC), according to a prespecified secondary analysis of patient-reported outcomes from the phase 3 TALAPRO-2 study (NCT03395197). The findings, published in The Lancet Oncology, support the clinical benefit of this combination therapy. 

“These results inform the risk-benefit assessment of the combination in patients with metastatic castration-resistant prostate cancer,” lead author Nobuaki Matsubara, MD, and colleagues wrote in their study.

Patients receiving talazoparib plus enzalutamide experienced a median time to definitive GHS/QoL deterioration of 30.8 months (95% CI, 27.0-not estimable [NE]), compared with 25.0 months (95% CI, 22.9-30.7) for those on placebo plus enzalutamide. The hazard ratio was 0.78 (95% CI, 0.62-0.99; two-sided P=.038), indicating a clinically meaningful delay in quality-of-life decline.

Patients received 0.5 mg talazoparib taken orally once daily with or without food, plus 160 mg enzalutamide taken orally once daily at the same time as talazoparib, or placebo plus enzalutamide both once daily. Treatment continued until progression, adverse event, patient decision to discontinue, or death.

A total of 805 patients were enrolled and randomly assigned to treatment irrespective of HRR gene alteration status. There were 395 patients in the treatment arm and 398 patients in the control arm. Median follow-up was 28.0 months (IQR, 23.9-31.7) in the treatment group and 26.8 months (IQR, 23.4-30.6) in the control group. 

Stratification factors were HRR gene alteration status (deficient vs nondeficient or unknown) and previous treatment with docetaxel or abiraterone acetate (Zytiga), or both (yes vs no) in the castration-sensitive setting.

The primary end point was radiographic progression-free survival by blinded independent central review and had been reported previously. Patient-reported outcomes were assessed as secondary endpoints in the patient-reported outcomes population, which comprised patients from the intention-to-treat population with a baseline patient-reported outcome assessment followed by at least one post-baseline patient-reported outcome assessment.

Overall, the median age of patients was 71 years (IQR, 66-76) with 33% of patients (264 of 793) aged 75 years or older; 62% of patients were White, 2% were Black or African American, and 31% were Asian.

Definitive deterioration in GHS/QoL was reported by 138 (35%) of 395 patients in the talazoparib plus enzalutamide group and 146 (37%) of 398 patients in the placebo plus enzalutamide group.

Reviewing the effect on urinary symptoms, the investigators reported the median time to definitive deterioration was not estimable (95% CI, NE-NE) in the treatment group vs 35.9 months (95% CI, 32.3-NE) in the control group. Modest treatment effects favoring placebo plus enzalutamide were observed in cancer-specific GHS/QoL and some symptom scales such as fatigue, nausea and vomiting, dyspnea, and appetite loss, but these did not reach the threshold for clinical meaningfulness (≥10-point change).

In the talazoparib plus enzalutamide group, the modest deterioration in GHS/QoL observed in the mixed-effects model (which includes fixed effects and random effects and is designed to handle longitudinal, repeated measures data) appears to be in contrast to the prolonged time to definitive deterioration in GHS/QoL observed in this study. However, the mixed-effects model provides 1 overall estimated mean and is influenced by all individual observations.

Definitive deterioration in GHS/QoL was reported by 138 (35%) of 395 patients in the talazoparib plus enzalutamide group and 146 (37%) of 398 patients in the placebo plus enzalutamide group.

The observed mean changes in GHS/QoL were greater initially after starting treatment with talazoparib plus enzalutamide, then stabilized. This pattern suggests that the combination might be tolerable with treatment modifications, such as dose reductions and transfusions. By contrast, the time to definitive deterioration analysis provides a more long-term view, and the prolonged time to definitive deterioration in GHS/QoL with talazoparib plus enzalutamide suggests improved disease control.

“Overall, these data suggest that the addition of a PARP inhibitor to androgen receptor pathway inhibitor therapy does not have any overall detrimental effect on health-related quality of life in patients with metastatic castration-resistant prostate cancer,” wrote Nobuaki Matsubara, MD, et al. “When considered with previously published efficacy benefit and safety profiles, this novel combination can be considered standard-of-care for first-line treatment of mCRPC,” Matusubara et al concluded.

REFERENCE:

Matsubara N, Azad AA, Agarwal N, et al. First-line talazoparib plus enzalutamide versus placebo plus enzalutamide for metastatic castration-resistant prostate cancer: patient-reported outcomes from the randomised, double-blind, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet Oncol. 2025;26(4):470-480. doi:10.1016/S1470-2045(25)00030-0