PARP Inhibitor Plus Androgen Receptor Signaling Inhibitor Combinations for Metastatic Castration-Resistant Prostate Cancer

A Quantitative Synthesis and Meta-Analysis

Results from a systematic review and meta-analysis of randomized clinical trials confirmed the efficacy and safety of PARP inhibitor plus androgen receptor signaling inhibitor combinations in the first-line setting for the treatment of patients with metastatic castration-resistant prostate cancer and BRCA1/2 and homologous recombination repair (HRR) gene mutations.

While the use of PARP inhibitors (PARPi) for patients with metastatic castration-resistant prostate cancer and HRR deficiency following failure on androgen receptor signaling inhibitor treatment is an established treatment, the clinical relevance of PARPi plus androgen receptor signaling inhibitor (ARSI) combinations for patients in this population is still uncertain.

In this systematic review and meta-analysis, randomized controlled phase 3 trials that compared PARPi plus ARSI with placebo plus ARSI in the first-line treatment for patients with metastatic castration-resistant prostate cancer from PubMed, EMBASE, SCOPUS, and Cochrane Library databases were included. The primary objectives in this analysis were to assess the radiographic progression-free survival (rPFS) and overall survival (OS) for the combination versus placebo plus ARSI among the patient population. A secondary objective was to assess the safety profile of combination.

There were 3 trials included (PROPEL, MAGNITUDE, and TALAPRO-2) with a total of 2601 patients. The PROPEL study evaluated a combination of abiraterone and olaparib and found the combination prolonged rPFS regardless of HRR status. In the HRR-positive subgroup, the median rPFS was not reached in the combination arm, vs 14 months for the control arm. TALAPRO-2 evaluated enzalutamide and talazoparib and with a median rPFS not reached for the combination arm vs 22 months for the control arm of group 1. In the HRR-positive subgroup, the median rPFS of the combination arm was 28 months, vs 16 months for the control arm. MAGNITUDE evaluated abiraterone and niraparib in a population of only HRR-positive patients (HRR-negative cohort was discontinued due to futility) and found the rPFS was significantly improved with the combination treatment.

Of the 3 trials, PROPEL and TALAPRO-2 were suitable for the meta-analysis. The pooled hazard ratio for rPFS was 0.62, favoring the comparison treatment over the control. The pooled hazard ratio for overall survival (OS) was 0.84, indicating a 16% reduction in risk of death among patients who were treated with the combination. The meta-analysis of rPFS of the combination treatment vs control among HRR-positive and HRR-negative subgroups, including all 3 trials, found a significant rPFS improvement among patients treated with the combination treatment, regardless of HRR status. MAGNITUDE and PROPEL were suitable to be included in the meta-analysis of BRCA-mutant patients which found the combination treatment significantly improved rPFS in comparison to the control.

The study authors concluded these data “support the use of PARPi + ARSI combinations in biomarker-unselected [metastatic castration-resistant prostate cancer]” but added “such combinations may be less clinically relevant in HRR-proficient cancers, especially considering the change in treatment landscape” which will leave “only a small proportion of patients [as] ARSI-naïve” in this setting.

Source:

Messina C, Giunta EF, Signori A, et al. Combining PARP inhibitors and androgen receptor signalling inhibitors in metastatic prostate cancer: A quantitative synthesis and meta-analysis. Eur Urol Oncol. Published online August 11, 2023. doi:10.1016/j.euo.2023.07.013