Editor's Note: From July 5 to 7, 2024, the 2024 Annual Progress Seminar of Chinese Clinical Oncology (BOC) and Beast of ASCO® 2024 China (BOC/BOA) was grandly held in Guangzhou. On the 6th, Professor Xiaojie Bian from Fudan University Shanghai Cancer Center shared the latest drug development progress for metastatic castration-resistant prostate cancer (mCRPC) from the 2024 ASCO annual meeting in the urologic tumor session, showcasing the new radioligand drug JNJ-6420 and the PROTAC AR-766.

JNJ-6420: A New Radioligand Therapy for mCRPC

Oncology Frontier: You shared research on the new radioligand therapy JNJ-6420 for mCRPC at the conference. Could you share the characteristics and research results of this new drug?

Professor Xiaojie Bian: JNJ-6420 is the first novel radioligand therapy targeting kallikrein-related peptidase 2 (KLK2). It primarily works by targeting KLK2, where Actinium-225 (225Ac) releases alpha particles to exert its antitumor effects. As we know, both KLK2 and KLK3 belong to the human kallikrein-related peptidase (KLK) family, with KLK3 being the prostate-specific antigen (PSA). KLK3 is an excellent diagnostic marker as a secretory protein. KLK2 has both secretory and membrane protein forms, with the membrane form being a crucial target for prostate cancer treatment.

The preliminary results of the phase I study of JNJ-6420 showed that the main toxicity was hematological, and lung toxicity was observed in the high-dose group. Therefore, subsequent studies adopted fixed doses or adjustable adaptive doses to control toxicity and improve efficacy data. The current objective response rate (ORR) achieved is 18%, PSA50 is 44%, and PSA90 is 9%, bringing initial benefits.

ARV-766: A New Generation PROTAC Therapy for mCRPC

Oncology Frontier: The ASCO meeting also announced the phase I/II study results of the new generation PROTAC protein degradation therapy ARV-766. What is its specific efficacy, and what value does it have for mCRPC?

Professor Xiaojie Bian: ARV-766 is a PROTAC drug targeting the androgen receptor (AR). As we know, PROTACs are formed by linking the ligand for the target protein (POI) with the ligand for the E3 ligase via a linker. It primarily binds to the target protein, ubiquitinates it, and then degrades it through recognition by the 26S proteasome within the cell. In recent years, several PROTAC drugs have been developed, but many failed at the phase I stage due to poor safety and less-than-expected efficacy.

ARV-766 shows an overall improvement in data compared to the earlier ARV-110, exhibiting better safety in clinical research. Regarding efficacy, we focus on PSA50 and PSA90. Among patients with ligand-binding domain (LBD) mutations, ARV-766 achieved a PSA50 of 43%. In patients with measurable lesions, we observed an ORR of 30%, including cases of complete response (CR) and partial response (PR). Overall, the research prospects for ARV-766 are very promising.

Implications of New Treatment Strategies for mCRPC and Urologic Tumors

Oncology Frontier: What insights do these new treatment strategies provide for the development of innovative drugs for mCRPC and urologic tumors?

Professor Xiaojie Bian: The data I shared at this BOC/BOA mostly come from phase I clinical studies, and the overall results are still immature. In recent years, with the continuous development of pharmaceutical technology, our development of therapeutic drugs for prostate cancer has not been limited to androgen receptors or radionuclides. New drugs such as poly ADP-ribose polymerase (PARP) inhibitors, radioligand conjugates (RDC), antibody-drug conjugates (ADC), and peptide-drug conjugates (PDC) have achieved certain efficacy, bringing more treatment hope to prostate cancer patients. This is the progress that we clinical researchers and drug development scientists hope to see, and we hope more patients can benefit from these new drugs.

Professor Xiaojie Bian

• Ph.D. and Postdoctoral Fellow in Oncology, Fudan University, Associate Chief Physician, Leader of the Comprehensive Treatment Group for Urologic Tumors, Leader of the Clinical Research Group for Urologic Tumors, Visiting Scholar at the Prostate Center, University of British Columbia, Canada
• Editorial Board Member of the CSCO Prostate Cancer Diagnosis and Treatment Guidelines
• Expert on the Chinese Expert Consensus on Advanced Prostate Cancer of CPCC
• Editorial Board Member of the CUA Testicular Cancer Guidelines
• Engaged in multidisciplinary comprehensive treatment and basic research of urologic tumors for a long time, specializing in the comprehensive treatment and clinical research of new drugs for prostate cancer, bladder cancer, and kidney cancer