Grewal Kabir, Dorff Tanya B, Mukhida Sagar S, Agarwal Neeraj, Hahn Andrew W
Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA.
Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA, USA.
Curr Treat Options Oncol. 2025 Apr 29. doi: 10.1007/s11864-025-01323-7.
Over the past few years, treatment for advanced prostate cancer has begun shifting away from a one-size-fits-all approach toward biomarker-based therapies for select groups of patients. This review highlights the role of poly-ADP-ribose-polymerase (PARP) inhibitors in metastatic prostate cancer, emerging strategies to target the androgen receptor (AR), and innovative therapies aimed at cell surface proteins, including radioligand therapies, bispecific T cell engagers, and antibody-drug conjugates. For patients with homologous recombination repair (HRR)-mutated metastatic castration-resistant prostate cancer (CRPC), we favor combining a PARP inhibitor (PARPi) with an AR pathway inhibitor (ARPI), provided they can tolerate a more aggressive treatment strategy. In our opinion, patients with BRCA1 or BRCA2 mutations who are unable to handle combination therapy benefit from PARPi monotherapy. We are enthusiastic about the potential of ongoing clinical trials for new AR-directed therapies, such as AR ligand-directed degraders and CYP11A1 inhibitors, in metastatic CRPC. These treatments are expected to be most beneficial for patients whose cancer continues to rely on AR pathway signaling, suggesting they might also be effective in earlier stages of the disease. Progress in drug development and understanding of protein structures has led to new therapies that target cell surface proteins predominantly found in prostate cancer. We use Lu-PSMA-617 for patients with PSMA avid metastatic CRPC who have progressed on an ARPI and a taxane chemotherapy. Additionally, we see promising potential in bispecific T-cell engagers (e.g., STEAP1-CD3 and PSMA-CD3) and novel radioligand therapies, including those utilizing actinium, to target these proteins. These advances show great promise in further enhancing survival for patients with metastatic prostate cancer.
在过去几年中，晚期前列腺癌的治疗已开始从一刀切的方法转向针对特定患者群体的基于生物标志物的疗法。本综述重点介绍了聚ADP核糖聚合酶（PARP）抑制剂在转移性前列腺癌中的作用、靶向雄激素受体（AR）的新兴策略以及针对细胞表面蛋白的创新疗法，包括放射性配体疗法、双特异性T细胞衔接器和抗体药物偶联物。对于具有同源重组修复（HRR）突变的转移性去势抵抗性前列腺癌（CRPC）患者，我们倾向于将PARP抑制剂（PARPi）与AR途径抑制剂（ARPI）联合使用，前提是他们能够耐受更积极的治疗策略。我们认为，无法接受联合治疗的BRCA1或BRCA2突变患者可从PARPi单药治疗中获益。我们对正在进行的转移性CRPC新AR导向疗法的临床试验潜力感到兴奋，例如AR配体导向降解剂和CYP11A1抑制剂。这些治疗预计对癌症仍依赖AR途径信号传导的患者最有益，这表明它们在疾病早期阶段也可能有效。药物开发的进展和对蛋白质结构的了解导致了针对主要在前列腺癌中发现的细胞表面蛋白的新疗法。我们将Lu-PSMA-617用于在ARPI和紫杉烷化疗后病情进展的PSMA高摄取转移性CRPC患者。此外，我们在双特异性T细胞衔接器（例如STEAP1-CD3和PSMA-CD3）以及新型放射性配体疗法（包括利用锕的疗法）中看到了靶向这些蛋白的有前景的潜力。这些进展在进一步提高转移性前列腺癌患者的生存率方面显示出巨大希望。
