Co-Inhibition of Androgen Receptor and PARP as a Novel Treatment Paradigm in Prostate Cancer—Where Are We Now?

SIMPLE SUMMARY: The past decade has seen the development and regulatory approval of a large number of new treatment options for advanced prostate cancer. Despite this, the two most used treatments—abiraterone and enzalutamide—have not been surpassed in efficacy, and eventually, all patients develop resistance to these treatments. Co-inhibition of androgen receptor (AR) and PARP proteins results in cancer cells’ inability to repair DNA. This combination approach has shown impressive early efficacy signals in preclinical and clinical settings and appears to be poised for a breakthrough. We review the science, data from clinical trials, and the future directions for this approach in this article. ABSTRACT: Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)—enzalutamide and abiraterone—have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25–30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020—rucaparib and olaparib—has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2–10 years.