Targeting reciprocal feedback inhibition: Apalutamide and everolimus in patients with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

204 Background: Studies in xenograft CRPC and PTEN-deficient prostate cancer models have shown synergistic anti-tumor activity of next-generation anti-androgens such as apalutamide when combined with PI3K/mTOR inhibitors such as everolimus. (Carver B et al., Cancer Cell 2011) The primary hypothesis of this study was that the combination of apalutamide with everolimus would overcome resistance to prior hormonal therapy with abiraterone acetate and prednisone (AAP). Methods: The primary endpoint in mCRPC patients with prior AAP was to evaluate the safety, pharmacokinetics (PK), and recommended phase 2 dose (RP2D) of fixed dose apalutamide 240 mg po qd when combined with everolimus 5 mg po qd (cohort 1, n = 3) and everolimus 10 mg po qd (cohort 2, n = 6). The plan was to expand to treat 40 patients at the RP2D. Results: Nine patients were enrolled in phase 1. The PK for the combination was consistent with historical data of either drug given as monotherapy. The most common treatment related adverse events were < = grade 2 fatigue (67%), diarrhea (56%), and anorexia (56%). In cohort 2, 1 patient had a DLT of grade 3 rash. The median time on treatment was 17 weeks (range 7-51+). The best response was SD in all 9 patients. Patients came off study for: progression (n = 3), investigator choice (n = 3) and toxicity unrelated to treatment (n = 2). Seven patients had detectable CTCs at baseline (EPIC Sciences). One patient had a rise in CTC number that then converted to undetectable and remained on study 37 weeks. One out of 6 evaluable patients had PTEN loss in tissue at baseline (MSK IMPACT) and remained on study 12 weeks. One patient with prior AAP and enzalutamide exposure has remained on study 51+ weeks with a > 50% decline in PSA (PTEN pending). Conclusions: Although the combination of apalutamide and everolimus was safe and well tolerated, the treatment response was similar to historical data of AAP followed by apalutamide alone. (Rathkopf D et al., ASCO 2014) We elected to close this study before expansion in favor of evaluating novel AR/PI3K pathway combinations in patients who have not yet been exposed to AAP. Drug provided by Janssen and Novartis. Trial support: PCF and MSK Experimental Therapeutics Center. Clinical trial information: NCT02106507.