Combination of PARP Inhibitors and Androgen Receptor Pathway Inhibitors in Metastatic Castration-Resistant Prostate Cancer

Abstract

Despite recent advances in the treatment of metastatic prostate cancer, progression to a castration-resistant state remains inevitable for most and prognosis is limited. Genetic testing for homologous recombination repair pathway alterations is recommended for all patients with advanced prostate cancer given that a mutation is present in up to 25% of cases. Poly(ADP-ribose) polymerase (PARPis) are now approved for use in patients with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor pathway inhibitor (ARPI) and harbour a germline or somatic homologous recombination repair mutation. Preclinical data support a synergistic effect with an ARPI and PARPi, and various ARPI-PARPi combinations have therefore been explored in phase III clinical trials. Despite heterogeneous findings, a clear hierarchy of benefit is evident, with patients harbouring a BRCA mutation deriving the greatest magnitude of benefit, followed by any homologous recombination repair mutation. The benefit in homologous recombination repair-proficient cohort is less clear, and questions remain about whether ARPI-PARPi combination therapy should be offered to patients without a homologous recombination repair mutation. With ARPIs now considered standard-of-care for metastatic hormone-sensitive prostate cancer, ARPI-PARPi combination therapy is currently being explored earlier in the treatment paradigm. The purpose of this review is to discuss the rationale behind ARPI-PARPi combination therapy, summarise the results of key clinical trials, and discuss clinical considerations and future perspectives.

Fig. 1

Mechanism of action of poly(ADP-ribose) polymerase inhibitors (PARPi) in a homologous recombination repair pathway-deficient (HRRd) cell resulting in synthetic lethality. BER base excision repair pathway, BRCA1 BReast CAncer gene 1, BRCA2 BReast CAncer gene 2, NER nucleotide excision repair pathway. Created with BioRender.com

Fig. 2

Mechanisms of action of poly(ADP-ribose) polymerase inhibitor (PARPis) and androgen receptor pathway inhibitors (ARPI) in advanced prostate cancer. AR-V AR splice variant, ARPI androgen receptor pathway inhibitor, AR androgen receptor, DHT dihydrotestosterone. ARPI suppresses AR activity (1), upregulates poly(ADP-ribose) polymerase (PARP) activity (2), and downregulates the homologous recombination repair (HRR) gene expression (3) thereby inducing a phenotype resembling HRR deficiency (BRCAness). PARPi disrupt single-strand DNA repair (4), leading to cytotoxic double-stranded DNA breaks, suppressing AR transcriptional activity (5), and may attenuate mechanisms of resistance to ARPIs mediated by co-deletion of RB1 and BRCA2 or AR-Vs (6). Created with BioRender.com