PSMA-based Therapies and Novel Therapies in Advanced Prostate Cancer: The Now and the Future.

Opinion statement: The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) is rapidly evolving with the advent of PSMA-targeted radioligand therapies (RLTs) and bispecific T-cell engagers (BiTEs). These novel approaches provide new hope for patients who have progressed on standard therapies. However, their full clinical potential will be realized only by addressing key challenges, including tumor heterogeneity, resistance mechanisms, immune-related toxicities, and the immunosuppressive tumor microenvironment. Additionally, the optimal sequencing of these therapies at different stages of disease remains an open question. While most of these interventions are currently introduced in late-stage, heavily pretreated patients, ongoing clinical trials are exploring their role in earlier disease settings, where they may be more effective in altering the natural history of disease. PSMA-based RLTs, such as 177Lu-PSMA- 617, have demonstrated promising efficacy, particularly in patients with high PSMA expression. However, the presence of PSMA-negative or heterogeneous tumors necessitates the development of additional biomarkers and combination strategies. The ongoing PSMAddition trial may establish RLTs as an earlier-line treatment in hormone-sensitive metastatic prostate cancer, potentially shifting the standard of care. Moreover, mitigating toxicities through radioprotective agents may aid in expanding their clinical utility. BiTE therapies offer a different but complementary mechanism of action, leveraging T-cell engagement to drive tumor cell destruction. While cytokine release syndrome (CRS) and immunogenicity remain significant hurdles, modifications such as low-affinity CD3 binding and optimized dosing regimens are showing promise. The potential synergy of BiTEs with immune checkpoint inhibitors and tumor microenvironment-modulating agents should be further explored to enhance therapeutic efficacy. Given these advancements, the future of mCRPC treatment likely lies in a personalized, multimodal approach that integrates PSMA-based RLTs, BiTEs, and complementary therapies at earlier disease stages. Strategic biomarker-driven patient selection and combination regimens will be essential in optimizing outcomes while minimizing resistance and toxicity.