The addition of the poly (ADP ribose) polymerase (PARP) inhibitor talazoparib to the androgen receptor signaling inhibitor enzalutamide achieved a statistically significant and clinically meaningful improvement in radiographic progression–free survival compared with placebo plus enzalutamide as first-line treatment of patients with metastatic castration-resistant prostate cancer. The radiographic progression–free survival benefit was observed regardless of homologous recombination repair (HRR) status. These findings from the primary analysis of the phase III TALAPRO-2 trial were presented at the 2023 ASCO Genitourinary (GU) Cancers Symposium.¹

“The effect of talazoparib plus enzalutamide was consistent across prespecified subgroups, including by age, performance status, Gleason score, site of metastasis, HRR status, or prior abiraterone or docetaxel,” said lead author Neeraj Agarwal, MD, FASCO, Professor of Medicine and Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment of men with metastatic castration-resistant prostate cancer, regardless of HRR gene alteration status,” he stated.

Neeraj Agarwal, MD, FASCO

Elena Castro, MD, PhD

However, formal discussant of this presentation, Elena Castro, MD, PhD, of Hospital Universitario 12 de Octubre, Spain, questioned this conclusion, noting that TALAPRO-2 as well as other trials have shown HRR status matters in patients treated with PARP inhibitors (see Expert Point of View). 

The placebo-controlled trial met its primary endpoint in patients with previously untreated metastatic castration-resistant prostate cancer. The risk of disease progression or death was significantly reduced by 37% with the combination of talazoparib plus enzalutamide, according to a blinded independent central review. At a median follow-up of about 24 months, median radiographic progression–free survival was not reached with the combination arm vs 21.9 months with placebo plus enzalutamide. (P < .001). Overall survival data are immature, and at this time, no difference was observed.

In patients with HRR-deficient metastatic castration-resistant prostate cancer who were treated with talazoparib plus enzalutamide (n = 85), median radiographic progression–free survival was 27.9 months vs 16.4 months with placebo plus enzalutamide (n = 84, P < .001). In patients who did not have HRR-deficient tumors or in whom HRR status was unknown, median radiographic progression–free survival was not reached with the combination therapy compared with 22.5 months with placebo plus enzalutamide (P = .004).

Among patients with HRR-nondeficient metastatic castration-resistant prostate cancer confirmed by prospective tumor tissue testing who received talazoparib plus enzalutamide, there was a 34% reduction in the risk of disease progression or death with talazoparib plus enzalutamide, and the median radiographic progression–free survival was not reached compared with 22.1 months for those in the placebo arm (n = 214, P = .009).

A previous phase II trial—TALAPRO-1—demonstrated that talazoparib monotherapy achieved durable antitumor activity and manageable safety in heavily pretreated patients with metastatic castration-resistant prostate cancer harboring HRR gene alterations, Dr. Agarwal explained. TALAPRO-2 evaluated talazoparib combined with enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer who were unselected for HRR status.

Study Details

A total of 805 patients were randomly assigned in a 1:1 ratio to receive treatment with talazoparib at 0.5 mg/d plus enzalutamide at 160 mg/d or placebo plus enzalutamide at 160 mg/d. Stratification factors were prior abiraterone or docetaxel treatment in the castration-sensitive setting (yes or no) and the presence of HRR gene alterations (deficient vs nondeficient or unknown).

The primary endpoint of TALAPRO-2 was radiographic progression–free survival. The key secondary endpoint was overall survival, and other secondary endpoints included time to cytotoxic chemotherapy, time to disease progression on the next line of therapy by investigator assessment, objective response rate, patient-reported outcomes, and safety.

At baseline, patient characteristics were well balanced between the treatment arms. In both arms, the median patient age was 71 years, and the median prostate-specific antigen (PSA) values were 18.2 ng/mL and 16.2 ng/mL with and without talazoparib, respectively. Metastatic disease sites included bone (86.8% and 84.9% in the talazoparib and placebo arms, respectively), lymph nodes (36.6% and 41.4%), lungs (11.2% and 15.1%), and liver (3.0% and 4.0%).

In both arms, about two-thirds of patients had an Eastern Cooperative Oncology Group performance status of 0. About 27 patients in both arms had prior treatment with abiraterone or docetaxel. HRR status was nondeficient or unknown in about 79% of patients in both arms of the study.

Tumor tissue was assessed for baseline HRR status in 804 of the 805 patients randomly assigned to treatment. In both arms, about 20% of patients had one or more alterations in the corresponding HRR genes.

Key Outcomes

The median time to PSA disease progression was 26.7 months with talazoparib and 17.5 months without (P = .002). The median time to use of cytotoxic chemotherapy was not reached in either arm, but there was a 51% reduction in the time to chemotherapy. The median time to disease progression on the next line of therapy was 36.4 months with talazoparib plus enzalutamide vs 35.3 months with placebo plus enzalutamide (hazard ratio = 0.77; 95% confidence interval = 0.61–0.98; P = .04).

Among 120 evaluable patients on the talazoparib arm, overall response rate was 61.7%; complete response rate was 37.5%, partial response rate was 24.2%, stable disease rate was 30.0%, and progressive disease rate was 5.8%. Among 132 evaluable patients treated with placebo plus enzalutamide, overall response rate was 43.9%, with complete response rate of 18.2%, partial response rate of 25.8%, stable disease rate of 28.8%, and a progressive disease rate of 22.7%. The overall survival data are immature, and the hazard ratio currently stands at 0.89 favoring talazoparib and enzalutamide.

Treatment-emergent adverse events were reported in 98.5% and 94.5% of patients in the talazoparib and placebo arms, respectively. Serious adverse events occurred in 39.4% of patients given talazoparib, including 19.6% with serious treatment-related adverse events; in the placebo arm, the rates were 26.7% and 3.0%, respectively.

The rates of grade 3 to 4 treatment-related adverse events were 71.9% and 40.6% with and without talazoparib, respectively. Grade 5 events occurred in 3.3% of the talazoparib arm compared with 4.5% in the placebo arm. No grade 5 treatment-related adverse events were reported in the talazoparib arm compared with 0.5% in the placebo arm.

Dose interruptions, reductions, and discontinuations of talazoparib occurred in 75.4%, 56.0%, and 19.1% of patients in the experimental arm, respectively. Corresponding rates in the placebo arm were 23.4%, 7.2%, and 12.2%, respectively. Most dose reductions of talazoparib occurred in the first 3 to 4 months due to anemia. Despite these early dose reductions, the permanent discontinuation of talazoparib due to adverse events was less common, and the median relative dose intensity in the talazoparib arm remained above 80%, which translates to a median talazoparib dose of 0.4 mg/d (the starting dose was 0.5 mg/d). Only 8.3% of patients had to permanently discontinue talazoparib due to adverse events.

Regarding treatment-related adverse events of special interest for talazoparib, one patient in the experimental arm experienced myelodysplastic syndrome during the safety reporting period, and another patient had acute myeloid leukemia during the follow-up period. Pulmonary embolism occurred in 2.5% of patients in the experimental arm and 0.7% of patients in the placebo arm.

According to patient-reported outcome measures, talazoparib plus enzalutamide significantly prolonged the time to clinically meaningful deterioration of global health status or quality of life. The median time to deterioration was 30.8 months with talazoparib plus enzalutamide compared with 25.0 months with placebo plus enzalutamide (P = .04). 

DISCLOSURE: TALAPRO-2 was sponsored by Pfizer in collaboration with Astellas Pharma. Dr. Agarwal has served as a consultant or advisor to Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, and Gilead Sciences; has received research funding from Bayer, Bristol Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, CRISPR Therapeutics, and Arvinas.

REFERENCE

1. Agarwal N, Azad A, Carles J, et al: TALAPRO-2: Phase 3 study of talazoparib + enzalutamide versus placebo + enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer. 2023 ASCO GU Cancers Symposium. Abstract LBA17. Presented February 16, 2023.