Recent Advances in the Treatment Landscape of Prostate Cancer
The therapeutic landscape of prostate cancer has undergone rapid transformation in the past several years, driven by advances in molecular subclassification, radioligand therapy, and precision-guided systemic interventions. Increasing recognition of the biological heterogeneity of prostate tumours—spanning androgen-driven adenocarcinoma to treatment-emergent neuroendocrine prostate cancer (NEPC)—has catalysed the integration of genomic profiling into routine decision-making. Landmark trials have demonstrated that homologous recombination repair (HRR) gene defects, particularly BRCA1/2, confer heightened sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition, leading to the approval of olaparib–abiraterone combinations in metastatic hormone-sensitive prostate cancer (mHSPC). These findings extend earlier observations in mCRPC and mark the first clear example of genotypically selected therapy moving upstream in the disease continuum.
Parallel progress has occurred in PSMA-targeted radioligand therapy (RLT). The VISION and PSMAfore trials have established Lu-177–PSMA-617 as an effective therapeutic modality that improves radiographic progression-free survival and overall survival, with expanding indications anticipated in pre-chemotherapy and mHSPC cohorts. Additionally, next-generation alpha-particle radiopharmaceuticals such as Actinium-225-PSMA are generating enthusiasm owing to their higher linear energy transfer and ability to overcome resistance to beta-emitting agents. Early-phase results indicate meaningful responses in patients with low PSMA expression or heterogeneous PSMA uptake, suggesting a potential role in genomically complex subtypes, including SPINK1-positive and lineage-plastic tumours.
The androgen receptor (AR) remains central to prostate cancer biology. Yet, emerging knowledge of AR mutations and splice variants has prompted the development of proteolysis-targeting chimeras (PROTACs) and AR-degrading agents. Compounds such as ARV-110 and ARV-766 have demonstrated PSA50 responses in heavily pretreated populations, particularly in tumours harboring AR point mutations that confer resistance to next-generation AR inhibitors. These therapeutics, together with antisense oligonucleotides targeting AR-V7, represent an impending paradigm shift for AR-dependent but treatment-refractory disease.
Immunotherapy—a longstanding challenge in prostate cancer due to its immunologically “cold” phenotype—is beginning to show renewed promise through bispecific T-cell engagers (BiTEs), checkpoint inhibitor combinations, and PSMA-directed CAR-T cell approaches. BiTEs targeting PSMA, STEAP1, or DLL3 have produced measurable responses in early trials, with toxicity mitigated by step-up dosing strategies. CAR-T cell platforms incorporating logic-gated receptors or safety switches are similarly advancing, with encouraging early signals even in mCRPC resistant to standard therapies. Moreover, personalized neoantigen vaccines, including mRNA-based modalities, have shown the capacity to generate immunogenic responses and may synergize with immunomodulatory therapies to reshape the tumour microenvironment.
Another area of rapid expansion involves epigenetic therapies and strategies addressing treatment-induced lineage plasticity—an increasingly recognized contributor to NEPC and aggressive-variant prostate cancer. The integration of EZH2 inhibitors, AURKA inhibitors, and DNA methylation modulators is yielding early evidence of re-sensitization to AR-targeted therapies and enhanced PSMA expression, with implications for both RLT effectiveness and targeted immunotherapy. These insights are reinforced by advances in spatial transcriptomics, which reveal ecologically diverse tumour–stroma interactions and enable identification of microenvironmental niches that govern therapeutic vulnerability or resistance.
Finally, artificial intelligence (AI) is increasingly incorporated into diagnostic and therapeutic workflows. AI-augmented multiparametric MRI interpretation improves lesion detection and reduces unnecessary biopsies, while radiomic-genomic prediction models are emerging as tools for forecasting response to AR pathway inhibitors, PARP inhibitors, and RLT. Together, these approaches align with the movement toward biomarker-driven, phenotype-specific management of prostate cancer, underscoring a future in which integrated molecular profiling and computational analytics guide individualized treatment strategies.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01919-6/abstract
https://pubmed.ncbi.nlm.nih.gov/36895851/
https://pubmed.ncbi.nlm.nih.gov/39115414/
https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5005
