TALAPRO-2 phase 3 trial reports overall survival benefit in HRR-altered metastatic prostate cancer

Evidence before this study

Before the TALAPRO-2 trial was started in December, 2017, we searched PubMed for relevant preclinical or clinical research published on DNA damage repair, homologous recombination repair (HRR), so-called BRCAness, novel hormonal therapies or androgen receptor pathway inhibitors (ARPIs), androgen receptor signalling inhibition, poly(ADP) ribose polymerase (PARP) inhibitors, and advanced prostate cancer. The worldwide incidence of prostate cancer is rising, and metastatic castration-resistant prostate cancer remains a lethal disease despite approvals of new agents. Therapies targeting androgen receptor signalling together with androgen deprivation therapy are the mainstay of standard of care for first-line treatment of metastatic castration-resistant prostate cancer. The prognosis is particularly poor for patients with metastatic castration-resistant prostate cancer harbouring HRR gene alterations. Since 2017, results from phase 2/3 investigational trials of PARP inhibitor monotherapy (olaparib, rucaparib, and talazoparib) have indicated efficacy of these agents in patients with BRCA-altered or HRR-altered (including BRCA) metastatic castration-resistant prostate cancer who had previously received treatment for metastatic castration-resistant prostate cancer. Two randomised phase 3 trials, PROpel () and MAGNITUDE (), which were conducted in parallel with the current study, investigated the combination of a PARP inhibitor (olaparib and niraparib, respectively) with the androgen biosynthesis inhibitor abiraterone acetate plus prednisone (or prednisolone in PROpel; AAP) as first-line treatment for metastatic castration-resistant prostate cancer versus AAP plus placebo. Results from the primary analysis of MAGNITUDE showed improved radiographic progression-free survival (rPFS) with niraparib plus AAP versus AAP plus placebo in patients with HRR-altered metastatic castration-resistant prostate cancer. In exploratory subgroup analysis of PROpel, rPFS benefit was noted with olaparib plus AAP versus AAP plus placebo in patients with HRR-altered metastatic castration-resistant prostate cancer. Results from the final overall survival analysis of PROpel and the interim and final analyses of MAGNITUDE showed differences in overall survival benefits for the combination versus AAP alone. In the subgroup of patients with HRR gene alterations in PROpel, olaparib plus AAP showed overall survival benefit versus AAP alone, although these analyses were not powered for statistical significance. The second interim analysis of the HRR-deficient cohort in MAGNITUDE showed no overall survival benefit for niraparib plus AAP versus AAP alone in patients with HRR gene alterations.

Added value of this study

The previously reported primary analysis of the prospectively assessed HRR-deficient cohort of TALAPRO-2 showed a statistically significant improvement in rPFS with talazoparib plus enzalutamide compared with enzalutamide plus placebo, as well as improvements in other secondary endpoints. In this prespecified analysis of the key alpha-protected secondary endpoint of overall survival of TALAPRO-2, talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in overall survival versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer harbouring tumour HRR gene alterations. Additionally, exploratory analyses indicated benefit of the talazoparib plus enzalutamide combination in subgroups of patients with or without tumour BRCA1/2 alterations, which extends the evidence of PARP inhibitor plus ARPI efficacy beyond BRCA1/2 alterations to non-BRCA1/2 HRR gene alterations. Exploratory post-hoc analyses reveal efficacy benefits across multiple individual HRR gene alteration subgroups, including among patients with tumour CDK12m, for whom PARP inhibitors had previously shown little benefit. No new safety signals were reported with long-term follow-up. These results add to our understanding of the efficacy of talazoparib plus enzalutamide in patients with metastatic castration-resistant prostate cancer harbouring tumour HRR gene alterations.

Implications of all the available evidence

As described previously, the overall survival results from the PROpel and MAGNITUDE trials differ from those reported in TALAPRO-2, the reasons for which are yet to be understood but might be related to differences in the characteristics of the individual PARP inhibitors (eg, PARP trapping ability) or the ARPI partner, the trial design (retrospectively or prospectively assessed HRR gene alterations), or differences in the dosing of these agents. Together with the results from the unselected cohort (reported separately), these data indicate that TALAPRO-2 is the only phase 3 trial to date to show statistically significant overall survival improvement with a PARP inhibitor plus ARPI combination versus an ARPI alone in patients with metastatic castration-resistant prostate cancer harbouring prospectively assessed tumour HRR gene alterations, as well as in unselected patients with metastatic castration-resistant prostate cancer. These data further establish the combination of talazoparib plus enzalutamide as a standard of care for patients with metastatic castration-resistant prostate cancer harbouring tumour HRR gene alterations.

Source: The Lancet