Combination therapies in the treatment of prostate cancer

In recent years, the therapeutic landscape of prostate cancer has transformed significantly, moving beyond single-agent approaches to employ combination therapies that maximize synergistic effects for enhanced patient outcomes. Since the introduction of docetaxel for metastatic castration-resistant prostate cancer (mCRPC), treatment options have expanded to include androgen receptor pathway inhibitors (ARPI), radioisotope therapies, PARP inhibitors, and cytotoxic agents, collectively improving survival and quality of life across prostate cancer stages. Combination strategies, particularly those integrating ARPI with chemotherapy or PARP inhibitors, have demonstrated significant clinical activity, especially in high-risk metastatic castration-sensitive (mHSPC) and BRCA1/2-mutated mCRPC patients. Clinical trials, such as PEACE-1 and ARASENS, reveal substantial survival benefits for three-drug regimens (ADT, docetaxel, and ARPI) in high-volume mCSPC. In mCRPC, the combination of ARPI and PARP inhibitors leverages synthetic lethality, notably enhancing outcomes in patients with DNA repair deficiencies. Additionally, emerging combinations with radioisotopes, ARPI and chemotherapy provide new avenues for cancer control, highlighting manageable toxicity profiles that facilitate broader patient applicability. However, the limited efficacy of immune checkpoint inhibitors, even in combination settings, underscores the need for tailored combinations based on prostate cancer’s unique molecular profile. This review synthesizes the latest evidence on combined systemic therapies in prostate cancer, underscoring the importance of strategically pairing agents to exploit distinct mechanisms of action while maintaining a favorable safety profile. The evolving model of combination therapy in prostate cancer presents promising insights for similar approaches in other solid tumors, marking a pivotal shift in oncological treatment paradigms.