PMID- 24008662 OWN - NLM STAT- MEDLINE DCOM- 20131204 LR - 20211203 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 109 IP - 7 DP - 2013 Oct 1 TI - A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naive castration-resistant prostate cancer. PG - 1711-6 LID - 10.1038/bjc.2013.530 [doi] AB - 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-naive 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-naive CRPC. FAU - Kruczek, K AU - Kruczek K AD - Department of Medicine, Advocate Lutheran General Hospital, Park Ridge, IL, USA. FAU - Ratterman, M AU - Ratterman M FAU - Tolzien, K AU - Tolzien K FAU - Sulo, S AU - Sulo S FAU - Lestingi, T M AU - Lestingi TM FAU - Nabhan, C AU - Nabhan C LA - eng PT - Clinical Trial, Phase II PT - Journal Article DEP - 20130905 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.21.77 (Prostate-Specific Antigen) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/adverse effects/therapeutic use MH - Disease Progression MH - Humans MH - Male MH - Middle Aged MH - Orchiectomy MH - Prospective Studies MH - Prostate-Specific Antigen/blood MH - Prostatic Neoplasms/*drug therapy MH - Protein Kinase Inhibitors/*adverse effects/*therapeutic use MH - Quality of Life MH - Sirolimus/adverse effects/*analogs & derivatives/therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Treatment Outcome PMC - PMC3790181 EDAT- 2013/09/07 06:00 MHDA- 2013/12/16 06:00 PMCR- 2014/10/01 CRDT- 2013/09/07 06:00 PHST- 2013/06/27 00:00 [received] PHST- 2013/08/02 00:00 [revised] PHST- 2013/08/09 00:00 [accepted] PHST- 2013/09/07 06:00 [entrez] PHST- 2013/09/07 06:00 [pubmed] PHST- 2013/12/16 06:00 [medline] PHST- 2014/10/01 00:00 [pmc-release] AID - bjc2013530 [pii] AID - 10.1038/bjc.2013.530 [doi] PST - ppublish SO - Br J Cancer. 2013 Oct 1;109(7):1711-6. doi: 10.1038/bjc.2013.530. Epub 2013 Sep 5.