Research in context
Evidence before this study
In the planning phase for TALAPRO-1, we searched PubMed in late 2015 to early 2016 for relevant preclinical or clinical research published on so-called BRCAness, DNA damage response, DNA damage repair (DDR), homologous recombination repair (HRR), synthetic lethality, poly(ADP-ribose) polymerase (PARP) inhibitors, and advanced prostate cancer. Prostate cancer remains the second most common cause of cancer-related death in men, with no curative treatment options available once patients develop metastatic castration-resistant prostate cancer. At study initiation, treatment options for men with metastatic castration-resistant prostate cancers included novel hormonal therapies (eg, enzalutamide, abiraterone), taxanes (docetaxel, cabazitaxel), radium-223, and sipuleucel-T. An unmet medical need remains for men with metastatic castration-resistant prostate cancers who have already received novel hormone therapy and taxane-based chemotherapy; some of these tumours carry alterations in DDR genes involved directly or indirectly in HRR that can sensitise to PARP inhibitors. Those alterations have been linked to worse prognosis. Several PARP inhibitors are being assessed for the treatment of metastatic castration-resistant prostate cancers with defective HRR gene alterations. The toxicity profile and efficacy or duration of sensitivity to PARP inhibitors might differ depending on specific HRR gene alterations; therefore, continued research with PARP inhibitors is warranted.
Added value of this study
To our knowledge, this study is the first international phase 2 trial to assess the antitumour activity and tolerability of talazoparib in men with metastatic castration-resistant prostate cancers with alterations in DDR genes involved in HRR who have been heavily pretreated. Antitumour activity was most notable against tumours with BRCA2 alterations, although partial or complete responses, stable disease, and prostate-specific antigen responses were also seen in tumours with alterations in BRCA1, PALB2, and ATM, which affirms that PARP inhibition has antitumour activity beyond the BRCA1 and BRCA2 subset. Our finding that homozygous loss is associated with enhanced antitumour activity might be crucial to interpreting antitumour activity results in gene-by-gene analyses from prostate cancer PARP inhibitor studies using multi-gene panels, including the TALAPRO-1 study.
Implications of all the available evidence
These data suggest that talazoparib has durable antitumour activity against lethal prostate cancers with various DNA repair defects that directly or indirectly impact HRR. This antitumour activity was observed even in men with very advanced prostate cancer who have exhausted most available treatment options. The favourable benefit–risk profile of talazoparib monotherapy against metastatic castration-resistant prostate cancers with alterations 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, randomised clinical trials, including in men with non-BRCA alterations.