Ayzman Ann, Pachynski Russell K, Reimers Melissa A
Department of Internal Medicine, Washington University in St. Louis, 660 S. Euclid Ave, Campus, Box 8056, St. Louis, MO, 63110, USA.
Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, 660 S. Euclid Ave, Campus, Box 8056, St. Louis, MO, 63110, USA.
Curr Treat Options Oncol. 2025 May;26(5):375-384. doi: 10.1007/s11864-025-01317-5. Epub 2025 Apr 23.
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.
随着前列腺特异性膜抗原（PSMA）靶向放射性配体疗法（RLTs）和双特异性T细胞衔接器（BiTEs）的出现，转移性去势抵抗性前列腺癌（mCRPC）的治疗格局正在迅速演变。这些新方法为在标准治疗中进展的患者带来了新希望。然而，只有通过应对关键挑战，包括肿瘤异质性、耐药机制、免疫相关毒性和免疫抑制性肿瘤微环境，才能实现它们的全部临床潜力。此外，这些疗法在疾病不同阶段的最佳序贯治疗仍是一个悬而未决的问题。虽然目前这些干预措施大多在晚期、经过大量预处理的患者中应用，但正在进行的临床试验正在探索它们在疾病早期阶段的作用，在这些阶段它们可能在改变疾病自然史方面更有效。基于PSMA的RLTs，如177Lu-PSMA-617，已显示出有前景的疗效，特别是在PSMA高表达的患者中。然而，PSMA阴性或异质性肿瘤的存在需要开发额外的生物标志物和联合策略。正在进行的PSMAddition试验可能会将RLTs确立为激素敏感性转移性前列腺癌的一线治疗方法，有可能改变治疗标准。此外，通过放射保护剂减轻毒性可能有助于扩大它们的临床应用。BiTE疗法提供了一种不同但互补的作用机制，利用T细胞衔接来驱动肿瘤细胞破坏。虽然细胞因子释放综合征（CRS）和免疫原性仍然是重大障碍，但低亲和力CD3结合和优化给药方案等改进措施显示出了前景。应进一步探索BiTEs与免疫检查点抑制剂和肿瘤微环境调节药物的潜在协同作用，以提高治疗效果。鉴于这些进展，mCRPC治疗的未来可能在于一种个性化的多模式方法，即在疾病早期阶段整合基于PSMA的RLTs、BiTEs和互补疗法。战略生物标志物驱动的患者选择和联合方案对于优化治疗效果、同时最小化耐药性和毒性至关重要。
