Optimizing treatment for metastatic castration-resistant prostate cancer: Food and Drug Administration-approved therapies, emerging strategies, and biomarker-driven approaches.

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal stage of disease progression despite substantial therapeutic advancements. Driven largely by androgen receptor (AR) signaling, prostate cancer eventually develops resistance to AR-directed therapies, necessitating alternative strategies. In recent years, several novel agents have received US Food and Drug Administration approval for mCRPC, including next-generation AR-signaling inhibitors, poly(adenosine diphosphate-ribose) polymerase inhibitors, targeted radioligand therapy, and immunotherapy. Although these treatments have extended survival, resistance mechanisms and optimal sequencing remain key challenges. Molecular profiling has uncovered distinct genomic alterations-such as defects in homologous recombination repair genes and mismatch repair alterations-that guide therapeutic decision making. In parallel, novel treatment modalities are being explored, including AR degraders, antibody-drug conjugates, T-cell engagers, and epigenetic modulators. This review critically evaluates current US Food and Drug Administration-approved therapies for mCRPC, examines emerging therapeutic strategies under clinical development, and discusses evolving biomarker-driven approaches that aim to personalize treatment and improve outcomes.