A randomized phase II study of apalutamide with or without carotuximab (ant-CD105) in metastatic, castration-resistant prostate cancer.
Authors: Posadas Edwin Melencio , Swami Umang , Dorff Tanya B. , Tighiouart Mourad , Wang Jasmine Jiemei , Zhu Yazhen , Tseng Hsian-Rong , Kohli Manish , Di Vizio Dolores , Bhowmick Neil 
Published: June 2023

TPS5107 Background: CD105 (endoglin) is a co-receptor for the transforming growth factor-beta (TGF-β) receptor family. TGF-β signaling is activated in response to castration and is a determinant of PCa epithelial cell death in response to castration. In prostate cancer, silencing of TGF-ß receptor type 2 (Tgfbr2) in cancer-associated fibroblasts (CAF) potentiates tumor progression and castrate resistance primarily by paracrine signaling mechanisms mediated by the bone morphogenic protein (BMP)-SMAD axis. Upregulation of CD105 is observed in the face of progression through AR suppression and can drive pro-survival, pro-metastatic pathways BMP-SMAD signaling. This is accompanied with an increase in neural differentiation and the generation of AR-splice variants. In model systems, suppression of CD105-mediated signaling reversed these behaviors and resorted sensitivity to AR suppression. Carotuximab is a humanized monoclonal antibody that potently inhibits CD105-mediated signaling. It was originally developed for clinical use as an anti-angiogenic agent and was found to have an acceptable toxicity profile. Given our previous work, we hypothesized that use of CD105 will restore sensitivity to AR inhibition in men who have developed early resistance to an AR signaling inhibitor (ARSI) that would result in a synthetic lethality from combination treatment that will manifest as an extension of progression free survival when compared to ARSI therapy alone. Methods: This study (NCT05534646) is open to men with metastatic, castration-resistant prostate cancer who have progressed on previous ARSI therapy. Patients with recent thrombotic and/or cardiovascular events are excluded. Patients are allowed to have had prior docetaxel only in the setting of castration sensitive disease. The study includes a safety lead-in of 10 patients on combination therapy based on our previous work with carotuximab with other ARSI in NCT03418324. This will ensure that the probability of starting the phase 2 dose with a safe dose is sufficiently high. The study then proceeds to a (1:1) randomized study of apalutamide with or without carotuximab (n = 90). Patients randomized to apalutamide alone are permitted to cross over to combination therapy at the time of radiographic progression. The primary endpoint of the study is radiographic progression free survival (rPFS) and is designed to detect a 45% difference in rPFS in the two arms with 81% power and two-sided alpha of 0.10. This study also includes extensive correlative studies focusing on circuating tumor cells and extracellular vesicles which will be enriched and studies using novel nanotechnology enabled methodologies from our group as well as cell free DNA studies which will be used identify those patients with the greatest benefits from this form of therapy to expedite the development of this therapeutic approach. Clinical trial information: NCT05534646 .