ESMO 2021: A First-in-Human Study of FOR46 in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

(UroToday.com) Treatment options for men with metastatic castration resistant prostate cancer (mCRPC) are limited beyond taxane chemotherapy and second-generation androgen pathway inhibitors. Moreover, resistance to these agents is associated with the emergence of small cell neuroendocrine prostate cancer in a subset of patients (tSCNC), portending poor prognosis. Additional therapeutic options are required for patients who have progressed on the multiple therapies approved in mCRPC, especially for patients with tSCNC.


Molecular profiling of tSCNC and mCRPC has revealed high RNA and protein expression of the cluster of differentiation 46 (CD46) molecule relative to other tissues.1 An antibody against a tumor-specific epitope of CD46 conjugated to the cytotoxic microtubule polymeration inhibitor MMAE (FOR46) has shown activity in preclinical prostate xenograft studies. In this abstract, Dr. Aggarwal and colleagues presented safety and early efficacy results from a first-in-human study of FOR46 in mCRPC (NCT03575819).

Patients with mCRPC, including tSCNC, who had progressed on one prior androgen pathway inhibitor but had not received chemotherapy for mCRPC were eligible for this study. A total of 33 patients were enrolled in a dose-escalating study. The median age of the cohort was 66, the median PSA was 41, and 7 patients had visceral organ metastases. Based on toxicity, dosing was changed to adjust body weight, and G-CSF was administered if grade 3 or higher neutropenia occurred in a previous cycle.

The maximum tolerated dose was 2.7 mg/kg by adjusted body weight. A third of patients experienced grade 4 neutropenia, and 6 patients experienced grade 3 neutropenia. A total of 42% of patients experienced infusion-related reactions, including 1 patient with a grade 3 reaction. Neuropathy occurred in 7 patients. Of the 24 patients that reached a dose of 1.2 mg/kg or higher, 38% sustained a PSA50 response, 63% had any PSA decline, and partial response was observed out of the 8 patients with measurable disease. Six of these patients had stable disease for varying degrees of time.

Based on these results, FOR46 is currently being evaluated in 2 mCRPC expansion cohorts, one for adenocarcinoma and the other for tSCNC.

Presented by: Rahul R. Aggarwal, MD, University of California at San Francisco, USA

Written by: Alok Tewari, MD, PhD – Genitourinary Medical Oncologist, Instructor in Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Twitter: @aloktewar during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.

References:

  1. Su Y., Liu Y., Behrens C. et al. "Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer." JCI Insight. 2018. 3(17): e121497.
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