Safety and preliminary efficacy analysis of the mTOR inhibitor ridaforolimus in patients with taxane-treated, castration-resistant prostate cancer.
BACKGROUND
Few options are available after taxane-based therapy in men with CRPC. Genetic alterations involving the mTOR pathway have been associated with CRPC development, raising the hypothesis that blocking mTOR signaling may be an effective targeted approach to treatment.


METHODS
In this open-label phase II study, the mTOR inhibitor Ridaforolimus was administered at a dose of 50 mg intravenous once weekly to 38 patients with taxane-treated CRPC. The primary end point was best overall response according to modified Response Evaluation Criteria in Solid Tumors guidelines. Serum prostate-specific antigen levels were prospectively monitored as a biomarker for cancer activity.


RESULTS
No objective responses were observed, but 18 patients (47.4%) had stable disease as their best response. Based on progression-free survival analysis, median time to progression with Ridaforolimus was 28 days (95% confidence interval, 27-29). Eight patients (21.1%) had stable disease as their best overall prostate-specific antigen response. The median number of days from first to last dose was 109.5 days (range, 1-442 days). Ridaforolimus was generally well tolerated, with a safety profile similar to that observed in patients with advanced malignancies. The most common side effects were typically mild or moderate in severity.


CONCLUSIONS
Ridaforolimus was generally well tolerated. Treatment did not produce objective responses, but stable disease was observed in some patients with taxane-treated CRPC. Alternative treatment regimens, such as combination therapy with a taxane or in a maintenance treatment paradigm, should be considered for further evaluation in this patient population.
The University of Texas Health Medical School, Memorial Hermann Cancer Center, Houston, USA. robert.amato@uth.tmc.edu
Robert J
RJ
Amato
George
G
Wilding
Glenn
G
Bubley
John
J
Loewy
Frank
F
Haluska
Mitchell E
ME
Gross
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D043823:Taxoids; D007987:Gonadotropin-Releasing Hormone; C515074:ridaforolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017430:Prostate-Specific Antigen; D020123:Sirolimus