Background and objective: The elucidation of prostate cancer biology and genomics has led to new therapies improving disease outcomes with novel androgen receptor (AR) pathway inhibitors (ARPIs), taxanes, and targeted therapeutics that require disease molecular stratification. Methods: We are presenting a narrative and qualitative synthesis based on a systematic search. Medline (PubMed) and Embase (OvidSP) were searched (October 1, 2024, covering 2019–2024) using keywords and Medical Subject Headings terms; ClinicalTrials.gov and ASCO/ESMO abstracts were also reviewed. The inclusion criteria were phase 1–3 studies on molecular targets or therapies for metastatic prostate cancer with posted results. The exclusion criteria included non-English articles, reviews, meta-analyses, commentaries, case reports, duplicates, nonhuman/preclinical studies, protocols, and studies lacking molecular targets. Key findings and limitations: Targeted therapies have emerged for specific molecular subtypes of advanced prostate cancer. For instance, poly(ADP)-ribose polymerase inhibitors target DNA repair defective prostate cancer (especially BRCA2 and PALB2 biallelic loss). Immune checkpoint inhibitors against PD-1/PD-L1 are effective in hypermutated prostate cancer cases, especially those with mismatch repair defective (MMRd) disease. Additionally, 177Lu-PSMA-617 impacts prostate-specific membrane antigen (folate hydrolase) expressing disease. Several other major therapeutic advances are envisioned in the near future, including targeting novel cell surface proteins with T-cell engager antibody constructs, immunoconjugates, and radiopharmaceuticals. Other rational therapeutic strategies are being pursued, targeting continued AR signalling; AR cofactors, for example, P300; PI3K/AKT signalling; the PRC2 complex protein including EZH2; as well as novel synthetic lethal strategies. Conclusions and clinical implications: A rapidly evolving standard of care is anticipated for metastatic prostate cancer, making it imperative that rational registration trial designs incorporating multipurpose biomarkers to accelerate anticancer drug development are pursued.
