Abstract 5327: KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both in vitro and in vivo

Abstract

Abstract Prostate cancer is the common cancer in men and the second leading cause of cancer-related deaths in men. This disease depends on dihydrotestosterone (DHT) which activates the androgen receptor (AR) signal. Endocrine therapy (including castration surgery, anti-androgen deprivation therapy or combined androgen blockade therapy) is a preferred treatment for prostate cancer. The treatment is very effective for the majority of patients at the initial stage, but after a median period of treatment for 14 to 30 months, most patients will gradually develop metastatic castration resistant prostate cancer (mCRPC) with a median survival of less than 20 months, and urgently need a further treatment. Androgen receptor antagonists in combination with anti-androgen drugs are currently the most effective drug treatment to manage mCRPC where castration has failed. Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide belong to this class of androgen receptor or androgen synthesis inhibitors. Here we show that KPG-121, a small molecule immunomodulator, significantly enhances the therapeutic effects of Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide in pre-clinical mCRPC tumor models. The phase 1 trials were initiated to evaluate the safety, PK profile and preliminary efficacy of the combinatorial therapy in the patients with metastatic castration resistant prostate cancer in the US (IND 134979). KPG-121 is a novel generation of Lenalidomide analogue. KPG-121 is structurally similar to lenalidomide but with stronger binding with CRBN target, enhanced immunomodulatory activity, better anti-proliferative and anti-angiogenic properties compared to lenalidomide. Results from in vivo metastatic castration resistant prostate cancer xenograft models demonstrated that KPG-121 at tested daily dose levels ranging from 1.0 mg/kg to 10 mg/kg in combination with Enzalutamide, Abiraterone Acetate, Apalutamide or Darolutamide significantly improved anti-tumor efficacy compared to the AR signaling inhibitors alone. In addition, KPG-121 showed favorable DMPK profiles and potentially manageable toxicity in pre-clinical IND enabling study. Citation Format: Chuansheng Ge, Lei Zhang, Baisong Liao. KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5327.