Editor's Note: For most prostate cancer patients, resistance to androgen deprivation therapy (ADT) inevitably develops within 18-36 months, progressing to castration-resistant prostate cancer (CRPC). This transition not only increases mortality risk but also poses a serious challenge to survival outcomes. The European Society for Medical Oncology (ESMO) Annual Meeting 2024, held from September 13 to 17 in Barcelona, Spain, showcased numerous studies on metastatic castration-resistant prostate cancer (mCRPC). Oncology Frontier - Urology Insight invited Dr. Xiaojie Bian from Fudan University Shanghai Cancer Center to share the latest advances.

• Study 1：Open-label, multicentre randomised trial of Radium223-docetaxel versus docetaxel-Radium223 sequence in metastatic castration resistant prostate cancer (mCRPC) with prospective biomarker evaluation (RAPSON study)
• Study 2：Clinical activity of BMS-986365 (CC-94676), a dual androgen receptor (AR) ligand-directed degrader and antagonist, in heavily pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)
• Study 3：Nivolumab 3mg/kg and ipilimumab 1mg/kg (nivo3/ipi1) in molecularly selected patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Dr. Xiaojie Bian：mCRPC represents an advanced stage of prostate cancer, with nearly 90% of patients experiencing bone metastases. Treating mCRPC is a focal point and challenge in current prostate cancer research. Available treatment options include novel endocrine therapies, chemotherapy, and radionuclide therapy; however, the optimal sequencing of these strategies remains unclear. Radium-223 is an alpha-particle-targeted therapy that selectively targets bone turnover areas in patients with bone metastases, emitting high-energy alpha particles to kill tumor cells while minimizing damage to surrounding healthy tissue. Previous ALSYMPCA studies showed that administering Radium-223 to mCRPC patients before docetaxel chemotherapy provided a longer overall survival compared to post-chemotherapy radionuclide treatment. The RAPSON study, presented at this ESMO meeting, provided evidence supporting the benefits of early initiation of Radium-223 for improving patient quality of life. The study found that, compared to the docetaxel-Radium-223 sequence, starting with Radium-223 followed by docetaxel improved patients’ quality of life and tolerance, offering compelling evidence for the early use of Radium-223 in mCRPC patients with bone metastases.

While mCRPC patients are generally resistant to AR pathway inhibitors, there is still potential in developing AR-targeted therapies. Proteolysis-targeting chimeras (PROTACs) are a new drug development technique that uses the cell’s ubiquitin-proteasome system to degrade proteins, with promising candidates like ONCT-534 and GTx-534. BMS-986365, an orally administered heterobifunctional therapy, has demonstrated antitumor activity in heavily pretreated mCRPC patients and has shown good tolerability and safety. Patients who had not undergone chemotherapy had a longer median radiographic progression-free survival (rPFS), and mCRPC patients with various AR LBD mutations showed clinical benefit. Dose-response studies suggest a PSA response dependent on dosage, indicating that future phase III trials will need additional evidence on dosing and safety.

Single-agent immunotherapy has previously shown limited efficacy for mCRPC; however, certain mCRPC patients with specific genetic characteristics may respond to combination immunotherapy. Preliminary results from the NEPTUNES study suggest that inflammation infiltration can serve as a potential predictive biomarker for determining whether previously treated mCRPC patients may benefit from dual immunotherapy. After molecular selection, mCRPC patients with MMRd, high TMB, BRCA2 mutations, or CDK12 inactivation benefited from dual immunotherapy, with MMRd patients showing better results with the nivo3/ipi1 regimen compared to monotherapy. This indicates a promising role for dual immunotherapy in mCRPC treatment. Previous research suggests that nivo1/ipi3 offers greater efficacy than nivo3/ipi1, though with more significant toxicities; thus, cautious dose selection and close monitoring are essential in clinical applications.

Dr. Xiaojie Bian

• PhD and Postdoctoral Fellow in Oncology, Fudan University
• Deputy Chief Physician
• Head of the Multidisciplinary Treatment Group for Urologic Oncology
• Head of the Clinical Research Group for Urologic Oncology
• Visiting Scholar, Prostate Centre, University of British Columbia, Canada
• Editorial Board Member, CSCO Prostate Cancer Treatment Guidelines
• Reviewing Expert, Chinese Expert Consensus on Advanced Prostate Cancer, CPCC
• Editorial Board Member, CUA Testicular Cancer Guidelines
• Experienced in the clinical and fundamental research of multidisciplinary treatment for urologic tumors, with expertise in prostate, bladder, and kidney cancer treatment and new drug clinical trials.

Weiwei Ma

• PhD Candidate, Urology Department, Fudan University Shanghai Cancer Center
• Visiting Scholar, University of Duisburg-Essen, Germany
• Conducting clinical work and research in tumors of the male urogenital system, with publications in Journal of the National Comprehensive Cancer Network and Advanced Science.