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Background: Treatments for CRPC are limited. CRPCs have activation of the PTEN-PI3K-AKT pathway increasing mTOR expression which drives cell proliferation. We hypothesize that combining the mTOR inhibitor R with the antiandrogen B in CRPC may improve response to second-line antiandrogens. We report a phase II trial of R/B in CRPC.

Methods: Patients (pts) with progressive CRPC and < 24 months (m) of prior B were treated with R/B. Treatment consisted of R 10 mg qd and B 50 mg qd. Primary endpoint was composite of prostate-specific antigen (PSA), bone and CT responses by standard criteria. This single-stage trial was designed to enroll 36 eligible patients to distinguish a 40% vs. 20% response (as expected for B alone; alpha=0.10, power=0.90).

Results: 36 pts had a median age of 68y (range 60-72). Median PSA was 22.2 ng/ml (range, 8.39-121.31). 30 pts (83%) had received prior B (median duration 7 m). 32 pts (89%) had metastastic disease; of these 30 (94%) had bone disease and 14 (44%) measurable disease. Any PSA decline was noted in 16/36 pts (44%). Maximum PSA declines of >30% and >50% were seen in 6 (17%) and 4 (11%) pts respectively. Median time to progression was 8w; 2 pts continue free of progression 32+ w. 33/36 pts have discontinued treatment: 24 progressed; 1 stopped for toxicity with stable disease (SD); 1 stopped due to intercurrent illness with SD; 7 stopped for other reasons prior to progression. Of the 24 pts that progressed: 17 (71%) had PSA progression; 7 (29%) measurable disease progression; 6 (25%) non-measurable progression. All 36 pts are evaluable for safety. Majority of adverse events were grade 1-2: mucositis 50%; rash 44%; fatigue 39%; diarrhea 25%; nausea 19%; CPK 14%. Most common grade 3 toxicities were hyperglycemia (n=3), fatigue (n=2), hemoglobin (n=2), hyponatremia (n=2), pain (n=2), and anal/perianal infection (n=2). No grade 4 toxicities were noted. 13 (36%) pts stopped for physician discretion or toxicity.

Conclusions: Novel methods of androgen suppression are under investigation. Androgen receptor signaling and PTEN-PI3K-AKT are co-stimulating growth pathways. R/B had low activity in CRPC possibly due to up-stream activation of AKT. Toxicity was moderate and this combination will not be pursued further.

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