Background:The mammalian target of rapamycin (mTOR) pathway is deregulated in castration-resistant prostate cancer (CRPC). We investigated the efficacy and toxicity of temsirolimus, an mTOR inhibitor, in chemotherapy-naïve CRPC.Methods:In this phase II open label study, eligible patients received IV temsirolimus at 25 mg weekly until objective disease progression, unacceptable toxicity or investigator’s discretion. Toxicity was assessed every 4 weeks and responses every 8 weeks. Primary end point was calculating the overall response (OR) rate as well as measuring stable disease (SD) to assess the overall clinical benefit calculated as OR+SD. Secondary end points included prostatic-specific antigen (PSA) changes and time to progression biochemically and radiographically. Correlative studies included prospective assessment of quality of life (QoL) using two previously validated scales.Results:Although the sponsor halted the study early, 21 patients were enrolled of which, 15 were evaluable for efficacy and OR. Median age was 74 (range: 57–89), median PSA was 237.5 ng ml−1 (range: 8.2–2360), visceral disease present in 11 patients (52%), and 17 patients (81%) patients had Gleason score (7–10). Two patients had a partial response (PR) and eight had SD. The OR was 13% (2/15) and the overall clinical benefit (OR+SD) was 67% (10/15). Median time to radiographic disease progression was 2 months (range 2–10 months). Biochemical response assessment was available for 14/15 patients. Any PSA decline was observed in four patients (28.5%; 4/14) with one patient (7%) having >50% PSA decline. Median time to progression by PSA was 2 months (range 1–10 months). With a median follow-up of 32 months, median overall survival (OS) was 13 months (range: 2–37) and three patients remain alive at the data cutoff (5/2013) for an OS of 14% at 4 years on an intent-to-treat analysis. Major non-haematologic toxicities included fatigue (19%) and pneumonia (14%). Main laboratory toxicities included hyperglycaemia (24%) and hypophosphatemia (14%). Also, 52% of enrolled patients had serious adverse events. Other toxicities were consistent with previously reported adverse events with temsirolimus. Despite these observed adverse events, temsirolimus did not adversely impact QoL.Conclusion:Temsirolimus monotherapy has minimal activity in chemotherapy-naïve CRPC.