(UroToday.com) At the 2026 ASCO GU Annual Symposium, Dr. Elise Cai presented results from a phase 1b/2 study evaluating FOR46, a monomethyl auristatin E antibody-drug conjugate targeting a tumor-specific epitope of CD46 that is highly expressed in metastatic castration-resistant prostate cancer (mCRPC), in combination with enzalutamide.
FOR46 is an antibody-drug conjugate directed against CD46, a tumor-specific epitope highly expressed in mCRPC. In pre-clinical models, CD46 cell surface expression is upregulated following treatment with androgen receptor pathway inhibitors (ARPIs), enhancing tumor cell sensitivity to FOR46. Based on this biologic rationale, the investigators sought to determine the safety and efficacy of FOR46 in combination with enzalutamide in patients with mCRPC.
In this study, eligible mCRPC patients had progression on ≥1 ARPI and no prior chemotherapy for CRPC. The phase 1b dose escalation study assessed adverse events and selected a recommended phase 2 dose (RP2D), utilizing a starting dose of FOR46 at 1.8 mg/kg adjusted body weight (ABW) every 3 weeks in combination with enzalutamide 160 mg daily.
The phase 2 primary endpoint was composite response rate, defined as either:
- PSA50 response
- Objective response by RECIST v1.1
Baseline CD46-targeted 89Zr-DFO-YS5 PET imaging was mandatory in phase 2 as an exploratory biomarker.
Between March 2022 and July 2025, 44 patients were enrolled. As of September 1, 2025, six patients remained on treatment. The baseline characteristics reflected a heavily pretreated population:
- Median age: 72 years (range 56–93)
- Median baseline PSA: 31.2 ng/mL (range 0.8–1147.7)
- 61% received ≥2 prior ARPIs
- 27% had visceral metastases
Seventeen evaluable patients were enrolled in phase 1b. The RP2D was established at FOR46 2.1 mg/kg ABW + enzalutamide 160 mg daily with G-CSF primary prophylaxis
Efficacy OutcomesIn the overall study cohort (phase 1b + 2), the median treatment duration was 3.5 months (range 0.0–17.8 months). Among evaluable patients, efficacy outcomes were as follows:
- Composite response rate: 21% (8/39)
- PSA50 response rate: 22% (8/37)
- Objective response rate: 9% (1/11)
The median radiographic progression-free survival (rPFS) was 6.6 months (95% CI 6.1–14.4). Importantly, outcomes differed by number of prior ARPIs:
- Median rPFS:
- 10.1 months (1 prior ARPI)
- 6.6 months (2 prior ARPIs)
- 5.1 months (3 prior ARPIs)
- Nominal p = 0.048
- PSA50 response rate:
- 40% (1 prior ARPI)
- 10.5% (2 prior ARPIs)
- 0% (3 prior ARPIs)
These data suggest greater anti-tumor activity earlier in the ARPI-resistant disease course.
SafetyGrade ≥3 treatment-related adverse events occurred in 19.5% (8 patients):
- Neutropenia (n=2)
- Anemia (n=2)
- Hyponatremia (n=2)
The most common any-grade treatment-related adverse events were:
- Fatigue: 68%
- Peripheral neuropathy: 56%
- Anorexia: 41%
- Dysgeusia: 32%
Treatment discontinuation due to TRAEs occurred in 37% of patients:
- 17% due to neuropathy
- 11% due to infusion reaction
Cumulative toxicities, particularly neuropathy, were dose-limiting for some patients.
Imaging BiomarkerBaseline 89Zr-DFO-YS5 PET demonstrated tumor uptake in both bone and soft tissue lesions, supporting on-target CD46 expression and providing proof-of-mechanism for the imaging strategy.
Dr. Cai concluded as follows:
- FOR46 in combination with enzalutamide demonstrates anti-tumor activity in mCRPC, particularly among patients with only one prior ARPI exposure.
- The median rPFS of 10.1 months in this subgroup and PSA50 responses of 40% suggest biologic activity when introduced earlier in the resistance sequence.
- The safety profile was consistent with prior phase 1 FOR46 monotherapy data, with neuropathy representing the key cumulative toxicity.
- Ongoing efforts are focused on predictive imaging and molecular biomarkers to better define the optimal patient population.
Presented by: Elise Y. Cai, MD, PhD, Hematology and Medical Oncology Fellow, Department of Medicine, University of California, San Francisco, CA, USA
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center, Tucson, AZ – @rksayyid on X during the 2026 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA, between February 26th and 28th, 2026. '
References:
- Laccetti AL, Chatta GS, Iannotti N, et al. Phase 1/2 study of EPI-7386 in combination with enzalutamide compared with enzalutamide alone in subjects with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(6_suppl):179.