Talazoparib emerging as new PARP inhibitor option in prostate cancer

Results from the phase 2 TALAPRO-1 study published in the Lancet Oncology show favorable antitumor activity with talazoparib in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) and DDR-HRR gene alterations, supporting ongoing phase 3 trials assessing the PARP inhibitor.¹

At a median follow-up of 16.4 months, the objective response rate (RESIST 1.1) was 29.8% (n = 31) among 104 evaluable patients. The most common gene alterations in this population were BCRA1/2. The confirmed complete response and confirmed partial response rates were 10% and 36% for the BCRA1 or BCRA2 groups, respectively, and 11% and 35%, respectively, for the BCRA2 group.

“The favorable benefit-risk profile of talazoparib monotherapy against metastatic castration-resistant prostate cancers with alteration in DDR genes either directly or indirectly involved in HRR in men previously treated with taxanes and novel hormone therapy supports the study of talazoparib in larger, randomized clinical trials, including men with non-BRCA alterations,” first study author Johann de Bono, MB CHB, PhD, MSC, head of drug development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and coauthors wrote.

As DNA damage response (DDR) alterations in genes that are directly or indirectly involved in homologous recombination repair (HRR) have been linked to worse prognosis, the continued research of the PARP inhibitors is crucial in helping men with mCRPC whose exposure to hormonal therapies and taxane-based chemotherapies was ineffective. According to the TALAPRO-1 researchers, , the DDR-HRR gene alterations are most likely to sensitize to talazoparib PARP inhibition.

Over the course of 29 months patients from hospitals, cancer centers, and medical centers of 14 different countries were enrolled in the open-label TALAPRO-1 trial. Between October 18, 2017, and March 20, 2020, 128 patients who had previously received at least 1 dose of TALAPRO-1 (safety population) and 104 patients with detectable soft tissue disease (evaluable population) participated in the study.

Patients were eligible if male and over the age of 18 and met the following criteria: progressive metastatic castration-resistant prostate cancers of adenocarcinoma histology measured by a recurrent PSA value of 2 μg/L, valid soft tissue disease or bone disease progression values, HRR alterations or DNA defects that resulted in sensitivity to a panel of 11 DDR-HRR gene alterations, an ECOG performance status of 0-2, exposure to 1 or 2 taxane-based chemotherapy regimens in the metastatic setting, and disease progression on abiraterone acetate (Zytiga) enzalutamide (Xtandi) or both in the mCRPC setting.

Eligible patients received 0.75 mg or 1 mg of oral talazoparib per day with the appropriate adjustments and care provided over time. This dosage continued until cancer progression or unacceptable toxicity was determined, or upon the withdrawal of consent or investigator’s discretion. Radiographic imaging initially assessed progression every 8 weeks, and then after the first 24 weeks, every 12 weeks. Safety assessments were also conducted on these individuals in the form of routine clinical laboratory tests.

Among evaluable patients with both baseline and post-baseline assessments, 80% (67 of 84 patients) had a reduction in tumor burden, 72% (69 of 96) had a reduction in PSA level, and 82% (37 of 45) had a reduction in circulating tumor cell count.

The median duration of talazoparib treatment was 6.1 months for the safety population (n = 127) and 6.2 months for the efficacy evaluable population. By the end of the study, 99% of the safety population had received talazoparib . The most frequently reported grade 3/4 treatment-emergent adverse were anemia (31%), thrombocytopenia (9%), and neutropenia (8%).Thirty-four percent of patients experienced serious treatment-emergent adverse events. There were no deaths resulting from talazoparib treatment.

As the first international phase 2 trial analyzing the antitumor activity and tolerability of TALAPRO-1 in this focused group, this study backs the ongoing phase 3 TALAPRO-2 trial NCT03395197investigating the combination of talazoparib and enzalutamide in men with mCRPC with or without HRR gene alterations. Another ongoing phase 3 trial, TALAPRO-3 (NCT04821622), is evaluating talazoparib plus enzalutamide in patients with DDR-deficient metastatic castration-sensitive prostate cancer.

Reference

1. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial [published online ahead of print August 10, 2021]. Lancet Oncol. doi: 10.1016/S1470-2045(21)00376-4