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Abstract Introduction Metastatic castration-resistant prostate cancer (mCRPC) causes over 375,000 deaths annually. Genomic heterogeneity, androgen receptor (AR) signaling dysregulation, DNA damage repair (DDR) deficiencies, and diverse resistance mechanisms limit conventional therapies, underscoring the need for individualized precision approaches. Content This review synthesizes the molecular drivers of mCRPC progression – including the AR signaling axis, DDR gene alterations, epigenetic modifications, and lineage plasticity – and the clinical evidence for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Key randomized trial data (VISION, PSMAfore, TheraP, ENZA-p) and real-world cohort outcomes, including institutional experience from West Virginia University in rural Appalachia, are critically appraised. Artificial intelligence-enhanced quantitative PSMA imaging, treatment resistance mechanisms, therapeutic sequencing, and theranostic infrastructure challenges are also addressed. Summary Lutetium-177 ( 177 Lu)-PSMA-617 significantly improves radiographic progression-free survival and overall survival in mCRPC. FDA expanded approval now enables earlier use in taxane-naïve patients after progression on an androgen receptor pathway inhibitor (ARPI) (PSMAfore: rPFS 11.6 vs. 5.6 months; HR 0.49). Real-world data confirm trial efficacy across diverse populations, including those with higher comorbidity burdens. Outlook Optimizing patient selection through quantitative AI-based imaging, identifying predictive molecular biomarkers, developing rational combination strategies, and expanding equitable access to radiopharmaceuticals are essential to maximizing the clinical benefit of PSMA theranostics.
Wang et al. (Tue,) studied this question.