Phase 2 trial launches of CD46-targeting ADC in mCRPC

Investigators have initiated a phase 2 trial (NCT06842498) of FG-3246, a potential first-in-class, CD46-targeting antibody drug conjugate for patients with metastatic castration-resistant prostate cancer (mCRPC), FibroGen announced in a news release.¹

The study is designed to evaluate the safety, efficacy, tolerability, and pharmacokinetics of FG-3246 in patients with mCRPC who progressed on a prior second-generation androgen receptor signaling inhibitor (ARSI) and had no prior taxane therapy in the mCRPC setting. The trial will also assess the ability of FG-3180, a companion PET imaging agent, to identify mCRPC lesions and predict response to treatment with FG-3246. The imaging agent uses the same CD46-targeted antibody used in FG-3246.

“With the transformation of FibroGen to a US-focused organization now complete and a robust cash runway into 2028, we are excited to advance our FG-3246 program and initiate the phase 2 monotherapy trial with the activation of the University of California San Francisco (UCSF) site,” said Thane Wettig, Chief Executive Officer of FibroGen, in the news release.¹ “FG-3246 demonstrated compelling clinical activity in patients that were heavily pre-treated, with a competitive radiographic progression free survival benefit in the phase 1 monotherapy study. We are confident that the dosing regimen of FG-3246, use of prophylactic G-CSF, and the enrollment of patients in earlier lines of treatment of mCRPC set us up to further demonstrate the potential of this program.”

In total, the phase 2, open-label, dose optimization trial plans to enroll 75 adult patients with mCRPC. Patients will be randomly assigned 1:1:1 to receive FG-3246 at either 1.8 mg/kg adjusted body weight (AJBW), 2.4 mg/kg AJBW, or 2.7 mg/kg AJBW. All patients will also take part in the sub-study evaluating FG-3180 prior to randomization.

To be eligible for the phase 2 study, patients need to have at least 1 metastatic lesion present on CT, MRI, or bone scan; serum testosterone levels less than 50 ng/dL during screening; and adequate organ function. Participants also need to have progressed on 1 prior treatment with a second-generation androgen receptor signaling inhibitor, which can include abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa).²

The primary end point for the study is the determination of an optimal dose level for a phase 3 trial based on efficacy, safety, and pharmacokinetic parameters. Secondary end points include radiographic progression-free survival (rPFS), disease control rate, prostate-specific antigen (PSA) 50 response, and PSA90 response.

An interim analysis of the data is planned once 12 patients in each of the 3 study arms have reached at least 12 weeks on the study or discontinued the trial.

“We anticipate results from the interim analysis of our phase 2 study in the second half of 2026,” added Wettig, in the news release.¹ “We also look forward to reporting the results from the ongoing investigator-sponsored study of FG-3246 in combination with enzalutamide in the fourth quarter of this year.”

Overall, final completion of the phase 2 trial is expected in March 2028.

Data on FG-3246

Data from the phase 1 study (NCT03575819) of FG-3246 were shared in April 2025.³ Overall, the agent demonstrated encouraging clinical activity while maintaining a manageable safety profile in patients with mCRPC.

The study enrolled a total of 56 patients with mCRPC across both the dose escalation and dose expansion phases. Those enrolled were biomarker unselected and heavily pretreated, with a median of 5 lines of prior therapy. The maximum tolerated dose was determined to be 2.7 mg/kg, using adjusted body weight, every 3 weeks.

According to the authors, “Dose-limiting toxicities included neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1).”

Across all dose levels, the most frequently reported grade 3 or higher adverse events were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). Grade 3 febrile neutropenia was also observed in 1 patient. No treatment-related deaths were reported.

A total of 40 patients were evaluable for efficacy, which was defined as patients with adenocarcinoma who received a dose of 1.2 mg/kg or higher. In these patients, the median rPFS was 8.7 months (range, 0.1 to 33.9). A PSA decline of at least 50% (PSA50) was observed in 36% of patients (14 of 39). A PSA50 response was also noted among 4 of 8 (50%) patients who received docetaxel in the castrative-sensitive setting.

Additionally, the confirmed objective response rate was 20% (5 of 25 RECIST-evaluable patients), and the median duration of response was 7.5 months. Those who responded to treatment were found to have significantly higher on-treatment frequency of circulating effector CD8⁺ T cells.

REFERENCES

1. FibroGen initiates phase 2 monotherapy trial of FG-3246, a first-in-class CD46 targeting ADC, in metastatic castration-resistant prostate cancer. News release. FibroGen, Inc. September 24, 2025. Accessed September 24, 2025. https://www.globenewswire.com/news-release/2025/09/24/3155319/33525/en/FibroGen-Initiates-Phase-2-Monotherapy-Trial-of-FG-3246-a-First-in-Class-CD46-Targeting-ADC-in-Metastatic-Castration-Resistant-Prostate-Cancer.html

2. A study of FG-3246 in participants with metastatic castration-resistant prostate cancer (mCRPC). ClinicalTrials.gov. Last updated July 14, 2025. Accessed September 24, 2025. https://clinicaltrials.gov/study/NCT06842498

3. Aggarwal RR, Vuky J, VanderWeele D, et al. Phase I, first-in-human study of FOR46 (FG-3246), an immune-modulating antibody-drug conjugate targeting CD46, in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2025:JCO2401989. doi:10.1200/JCO-24-01989