Phase II study of bipolar androgen therapy combined with sipuleucel-T for patients with metastatic castration resistant prostate cancer (mCRPC).

e17081 Background: Bipolar androgen therapy (BAT) is an investigational therapy comprising monthly supraphysiologic testosterone injections and continuous androgen deprivation therapy (ADT). BAT demonstrated clinical activity in patients with metastatic castration resistant prostate cancer (mCPRC) progressing on abiraterone acetate (Denmeade S et al JCO 2021). Preclinical studies showed that dihydrotestosterone increases the cytotoxicity of macrophages against prostate cancer cell lines in a concentration-dependent manner (Lee GT et al Endocrinology 2019). Sipuleucel-T, an autologous cellular immunotherapy manufactured from peripheral blood mononuclear cells cultured with PA2024, Prostatic Acid Phosphatase linked to GM-CSF, improved overall survival (OS) in patients with mCRPC. Interferon-gamma (IFN-g) enzyme-linked immunosorbent spot (ELISPOT) response to PA2024 was an immune response parameter that had the strongest correlation with OS benefit (Sheikh N et al. CII. 2012). The ELISPOT response was, however, detected only in 50% of patients treated with sipuleucel-T. We hypothesized that treatment with BAT prior to sipuleucel-T could enhance ELISPOT response rate. Methods: Patients with progressive mCRPC and with clinical indication for sipuleucel-T were enrolled. The key eligibilities included PSA < 20ng/mL, no opioid use for cancer-related pain, no hepatic metastasis, no prior chemotherapy for mCRPC, and no active autoimmune disease. Patients continued with ongoing ADT and received testosterone cypionate 400mg intramuscularly every 4 weeks until they are no longer deriving clinical benefit. Sipuleucel-T started after two 4-weekly testosterone injections and administered every 2 weeks for 3 cycles. Research blood was collected before each testosterone injection and each sipuleucel-T infusion. The primary endpoint was ELISPOT response, defined as > 10 IFN-g response spots to the PA2024 antigen. Results: Compared to the historical control of 50%, PA2024 ELISPOT response rate, eleven of 11 (100%) evaluable patients achieved positive ELISPOT responses ( > 10 spots) to PA2024 antigen. The mean number of spots was 232 (95% Confidence Interval (CI) 147, 317). 100% of patients achieved T cell proliferation response to PA2024 antigen ( > 12 Stimulation Index (SI)). Mean SI (95% CI) was 23 (17,30). One of two RECIST-evaluable patients achieved confirmed PR. Two of 11 evaluable patients had PSA50 responses. No grade 3 or higher adverse events or serious adverse events were observed. Conclusions: BAT followed by sipuleucel-T is safe and effective in potentiating immune response to Sipuleucel-T. Encouraging clinical activity has been observed. The study is currently enrolling to the second stage of the Simon’s design. Clinical trial information: NCT06100705 .