4588 Background: Everolimus is a potent, orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR) pathway and has shown activity in preclinical cancer models. This phase II study investigated the activity of single agent everolimus as first-line treatment in patients (pts) with mCRPC.
METHODS
Pts with rising PSA while castrate (testosterone < 50ng/dl) and a PSA-doubling time (PSA-DT) of ≥ 55 days, no prior chemotherapy, and adequate organ function were eligible. Continuation of androgen deprivation therapy was required. Everolimus was administered continuously at a dose of 10mg daily. The primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA increase ≥ 25% over baseline, and no progression of metastases on imaging or clinically. Secondary endpoints included adverse events (AE), PFS, response (PSA, measureable disease), and overall survival. 32 evaluable pts were needed in a Simon's two stage minimax design with a power of 90% and a significance level of 10% to test a PFS rate at 12 weeks of ≤ 15% (H0) vs. ≥ 35% (H1). Accordingly, ≥ 8 pts without progression at 12 weeks were needed to reject H0. New predictive serum biomarkers are evaluated by proteomics and PTEN status / PI3-kinase-dependent pathway activation is monitored in tumor tissue.
RESULTS
37 pts were enrolled at 10 Swiss centers between 9/09 and 8/10. Median age was 69 (range 47-85) years, performance status was 0 in 78%, and 1 in 22%; median PSA was 50µg/l (range 7-2039µg/l), 16% of pts had visceral metastases. 12 pts (32%; 95% CI 18-50%) remained free of progression at 12 weeks. PSA decline ≥ 30% and ≥ 50% was seen in 4 (11%) and 1 (3%) pts, respectively. Treatment related AE's were as expected and included mucositis/stomatitis, fatigue, diarrhea (in > 20%, all grades). Alveolitis/pneumonitis occurred at ≤ G2. G3 events occurring in more than 1 pt were anemia and lymphopenia. In depth analysis of lymphocyte subpopulation and function will be presented.
CONCLUSIONS
To our knowledge this is the first trial testing everolimus as first line monotherapy in patients with mCRPC which shows encouraging activity and manageable toxicity. Further studies are warranted.