Evaluation of novel treatments for metastatic castration-resistant prostate cancer

INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with a median overall survival of approximately 2 years. Although major therapeutic advances have been achieved over the past two decades, many effective treatments have shifted to earlier disease settings, and significant unmet needs persist in the mCRPC population. AREAS COVERED: This narrative review is based on a structured literature search of PubMed/MEDLINE and Embase covering publications from January 2020 to October 2025, supplemented by ClinicalTrials.gov and major oncology congress abstracts (ASCO and ESMO). The molecular landscape of mCRPC, currently approved therapies, and emerging treatment strategies are discussed, including next-generation androgen receptor-targeted agents, PTEN/PI3K/AKT/mTOR pathway inhibitors, PSMA-targeted radioligand therapies, antibody-drug conjugates, CDK4/6 inhibitors, epigenetic modifiers, and novel immunotherapeutic approaches. EXPERT OPINION: The therapeutic landscape of mCRPC has expanded substantially; however, treatment resistance and the absence of validated sequencing strategies continue to pose major challenges. Advancements in this field will rely on improved molecular profiling, biologically rational combination strategies, and the incorporation of predictive biomarkers to enable personalized treatment decisions. Concurrently, earlier integration of targeted therapies, radioligand approaches, and biomarker-enriched clinical trial designs is likely to reshape treatment paradigms and enhance long-term clinical outcomes.