A novel CD46-targeting antibody-drug conjugate (ADC) has demonstrated encouraging clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC), according to results from a phase 1 trial published in the Journal of Clinical Oncology.
FG-3246 (formerly FOR46), developed by FibroGen, showed promising anti-cancer activity while maintaining a manageable safety profile in a heavily pre-treated patient population, potentially offering a new treatment approach for advanced prostate cancer patients with limited options.
Trial Results Show Promising Efficacy
The first-in-human, open-label phase 1 trial enrolled 56 biomarker-unselected patients with mCRPC across five clinical sites in the United States. Participants had received a median of five prior lines of therapy before entering the study.
Among the 25 patients evaluable for RECIST criteria, the confirmed objective response rate was 20%, with all responses observed at doses of 2.7 mg/kg or higher. The disease control rate reached an impressive 80%, with 48% of patients maintaining treatment for longer than 24 weeks.
Dr. Rahul Aggarwal, Professor of Medicine at the University of California, San Francisco and principal investigator of the study, expressed enthusiasm about the findings: "This is the first clinical trial targeting CD46 in patients with prostate cancer, and the totality of the data highlights the promising potential of FG-3246 anti-cancer activity, especially when considering the unselected, heavily pre-treated patient population in the trial."
The study also reported a median radiographic progression-free survival (rPFS) of 8.7 months across all 40 patients in the efficacy analysis set. Additionally, 36% of evaluable patients (14 of 39) achieved a prostate-specific antigen (PSA) decline of at least 50%.
Notably, among eight evaluable patients who had previously received docetaxel in the castration-sensitive setting, four (50%) achieved a confirmed PSA50 response, suggesting potential activity in this specific subgroup.
Safety Profile and Dosing
The maximum tolerated dose was determined to be 2.7 mg/kg using adjusted body weight, administered intravenously every three weeks.
The most frequent adverse events were consistent with other MMAE-based ADCs, including infusion-related reactions (48.2%), neutropenia (41.1%), and peripheral neuropathy (32.1%). Across all dose levels, the most common grade 3 or higher adverse events included neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%).
Dose-limiting toxicities included neutropenia (n=4), febrile neutropenia (n=1), and fatigue (n=1). One patient experienced grade 3 febrile neutropenia, but no treatment-related deaths were reported.
Researchers noted that ocular adverse events were infrequent, which may distinguish FG-3246 from other MMAE-based ADCs.
Targeting CD46 in Prostate Cancer
CD46, a cell receptor target present at high levels in prostate cancer and other tumor types, demonstrates limited expression in most normal tissues. The study found that 12 of 15 (80%) evaluable baseline tumors were positive for CD46 expression by immunohistochemistry.
FG-3246 is comprised of an anti-CD46 antibody, YS5, linked to the anti-mitotic agent MMAE, which is a clinically and commercially validated ADC payload.
Interestingly, patients who responded to FG-3246 treatment were found to have a significantly higher frequency of effector T cells and a lower frequency of immunosuppressive myeloid cells, suggesting potential immune-modulating effects of the therapy.
Development Plans
"FG-3246 represents a potential first-in-class, non-PSMA approach to treating mCRPC and we, along with the medical community, are excited about the potential for CD46 to become a next generation target in the prostate cancer treatment paradigm," said Thane Wettig, Chief Executive Officer of FibroGen.
The company plans to advance FG-3246 in the clinic with a phase 2 monotherapy dose optimization study by mid-2025. Additionally, FG-3246 is being evaluated in combination with enzalutamide in an investigator-sponsored study, with topline results from the phase 2 portion expected in the second half of 2025.
Addressing an Unmet Need
Prostate cancer remains the second most common malignancy in men, with approximately 13% of men being diagnosed with the disease during their lifetime. There are about 65,000 drug-treatable mCRPC cases in the U.S. annually, and the five-year survival rate in mCRPC is approximately 30%.
The development of novel therapies like FG-3246 is crucial for addressing the significant unmet need in this patient population, particularly for those who have progressed on existing treatments.
As Dr. Aggarwal noted, "The trial results provide key insights into the potential clinical impact of targeting CD46 in the treatment of mCRPC and support its further development in this disease space with high unmet need."
