Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

Abstract

The treatment landscape of advanced prostate cancer has completely changed during the last decades. Chemotherapy (docetaxel, cabazitaxel), androgen-receptor signaling inhibitors (ARSi) (abiraterone acetate, enzalutamide), and radium-223 have revolutionized the management of metastatic castration-resistant prostate cancer (mCRPC). Lutetium-177-PSMA-617 is also going to become another treatment option for these patients. In addition, docetaxel, abiraterone acetate, apalutamide, enzalutamide, and radiotherapy to primary tumor have demonstrated the ability to significantly prolong the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Finally, apalutamide, enzalutamide, and darolutamide have recently provided impactful data in patients with nonmetastatic castration-resistant disease (nmCRPC). However, which is the best treatment sequence for patients with advanced prostate cancer? This comprehensive review aims at discussing the available literature data to identify the optimal sequencing approaches in patients with prostate cancer at different disease stages. Our work also highlights the potential impact of predictive biomarkers in treatment sequencing and exploring the role of specific agents (i.e., olaparib, rucaparib, talazoparib, niraparib, and ipatasertib) in biomarker-selected populations of patients with prostate cancer (i.e., those harboring alterations in DNA damage and response genes or PTEN).

Keywords: LuPSMA; PARP inhibitors; androgen-receptor signaling inhibitors; chemotherapy; ipatasertib; metastatic castration-resistant prostate cancer; metastatic hormone-naïve prostate cancer; metastatic hormone-sensitive prostate cancer; nonmetastatic castration-resistant prostate cancer.

Figure 1

Possible sequencing scenarios in patients with mHSPC initially treated with: (a) Docetaxel; (b) ARSi; (c) Radiotherapy to the primary tumor. Patients with small-cell or neuroendocrine prostate cancer should start a first-line treatment with platinum-based chemotherapy. ARSi: androgen-receptor signaling inhibitors. * Other treatments can include: radium-223 for patients with symptomatic bone metastases; lutetium-177-prostate-specific membrane antigen (PSMA)-617 (LuPSMA) after regulatory approval; olaparib or other PARP-inhibitors for patients with DNA damage and response (DDR) genes defects; pembrolizumab or other immunotherapy for patients with microsatellite instability (MSI)-high/mismatch-deficient prostate cancer; sipuleucel-T (only USA); and mitoxantrone for palliation in symptomatic patients who cannot tolerate other therapies.