Metastatic castrate-resistant prostate cancer: a new horizon beyond the androgen receptors

Systemic chemotherapy and second-generation androgen receptor-axis targeted therapies have been in the forefront of management for metastatic castrate-resistant prostate cancer (mCRPC) patients with low or high symptom burden. However, in the recent past, due to improvement in molecular characterization, management of mCRPC has witnessed long strides of advancement. We aim to review the novel nonhormonal and nonchemotherapeutic treatment options.

Poly (ADP-ribose) polymerase inhibitors (PARPis) such as olaparib and rucaparib have been recently approved by the US FDA for use in mCRPC with germline or somatic mutations in homologous recombination repair. The combination of PARPi with androgen receptor axis-targeted agents (ARAT) or dual ARAT-based therapy has shown superior radiographic progression-free survival as a first-line treatment. A combination of AKT inhibitor ipatasertib and abiraterone has shown improvement in radiographic progression-free survival as a first-line treatment. Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical like 177Lu-PSMA-617, a beta particle emitter has demonstrated improvement in overall survival in mCRPC patients pretreated with ARAT or taxanes. Although immune checkpoint inhibitors are being tested in mCRPC, there is no robust evidence to support this premise.

These new agents have widened the treatment options for mCRPC patients. Overall treatment should be focused on improving survival while limiting the deterrent effect on the quality of life.