CHICAGO — Patients with castration-resistant prostate cancer had limited side effects and in many cases a drop in prostate-specific antigen expression with galeterone (TOK-001), a small-molecule oral drug, according to phase I data presented at the AACR Annual Meeting 2012, held here March 31 - April 4.
Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer that occurs when the disease progresses after treatment with androgen deprivation therapy. Galeterone works against CRPC by blocking the androgen receptor, reducing levels of the ligand that binds to the receptor and degrading the androgen receptor protein.
"This drug has a novel combined mechanism of action," said co-lead researcher R. Bruce Montgomery, M.D., associate professor of medical oncology at the University of Washington School of Medicine in Seattle, Wash. "Cancer cells are sly and mutate to get around drugs. The fact that this drug hits the prostate cancer cell in three different ways may help prevent resistance. It is a well-tolerated drug that could potentially be more effective than drugs we have now."
In the ARMOR1 study, Montgomery and colleagues assigned 49 patients with CRPC to one of eight dose regimens in single or split oral escalation doses of 650 mg, 975 mg, 1,300 mg, 1,950 mg or 2,600 mg every day for 12 weeks. None of the patients had received chemotherapy for their prostate cancer.
Researchers reported that no patients reached a maximum tolerated dose. Most side effects were minor and included fatigue, nausea and diarrhea. Researchers observed transient, nonserious elevated liver function tests in 15 patients, many of whom were asymptomatic. Eleven of these patients temporarily stopped galeterone treatment, and six returned to treatment with no recurring liver function test elevations. One serious complication occurred involving rhabdomyolysis in the setting of simvastatin therapy and underlying renal insufficiency.
In early efficacy tests, 49 percent of patients had prostate-specific antigen (PSA) reductions of 30 percent or more; 11 of these patients had reductions of 50 percent or more. In addition, CT scans revealed reduction in tumor size for some patients.
"Because the androgen receptor controls PSA expression, improved PSA response shows that the drug is getting to the target," said Montgomery. "For the majority of patients, to reduce their PSAs by 30 percent or more is quite good in a phase I dose-finding trial."
Researchers will investigate long-term safety and an assessment of efficacy in a phase II study that Tokai Pharmaceuticals has planned for the second half of 2012.
Press registration for the AACR Annual Meeting 2012 is free to qualified journalists and public information officers: http://www.aacr.org/PressRegistration.
Follow the AACR on Twitter: @aacr #aacr
Follow the AACR on Facebook: http://www.facebook.com/aacr.org
About the AACR
Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR's membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.
For more information about the AACR, visit www.AACR.org.
Presenter: R. Bruce Montgomery, M.D.
Abstract Number: CT-07
Title: ARMOR1: Safety of galeterone (TOK-001) in a phase I clinical trial in chemotherapy naïve patients with castration resistant prostate cancer (CRPC).
Author Block: Mary-Ellen Taplin1, Franklin Chu2, Jodie P. Morrison3, Roberto Pili4, Matthew B. Rettig5, Joe Stephenson6, Nicholas J. Vogelzang7, R. Bruce Montgomery8. 1Dana-Farber Cancer Institute, Boston, MA; 2San Bernardino Urological Associates, San Bernadino, CA; 3Tokai Pharmaceuticals, Cambridge, MA; 4Roswell Park Cancer Institute, Buffalo, NY; 5David Geffen School of Medicine at UCLA, Los Angeles, CA; 6Cancer Centers of the Carolinas, Greenville, SC; 7Comprehensive Cancer Centers of Nevada & US Oncology Research, Las Vegas, NV; 8University of Washington, Seattle, WA.
Introduction: Galeterone is an orally available, semi-synthetic steroid analog for the treatment of castration-resistant prostate cancer (CRPC) that inhibits prostate cancer growth through a triple mechanism-of-action by: a) inhibiting CYP17 lyase activity; b) binding to and inhibiting the androgen receptor; and, c) degrading androgen receptor protein. ARMOR1, a phase I dose escalation study in men with chemotherapy naive CPRC, evaluated the safety of galeterone. Preliminary efficacy was also assessed by measuring changes in prostate-specific antigen (PSA) levels and tumor response.
Methods: Forty-nine men with metastatic and non-metastatic chemotherapy-naïve CRPC were enrolled in the ARMOR1 study. Patients were enrolled with confirmed adenocarcinoma of the prostate and disease progression during androgen ablation therapy. Patients ranged in age from 48 to 93 years old and had ECOG status of 0 or 1. Patients were randomized to one of eight dose escalation cohorts receiving galeterone capsules in single or split oral doses of 650, 975, 1300, 1950, or 2600mg daily for 12 weeks. After 12 weeks, eligible patients could continue treatment in an extension phase.
Results: Maximum tolerated dose was not reached. The frequency of patients with Grade 1 and Grade 2 adverse events (AEs) reported by body system was 58% and 30% respectively. The most commonly reported AEs by patient were fatigue (36.7%), aspartate aminotransferase (AST) increase (32.7%), alanine aminotransferase (ALT) increase (30.6%), nausea (28.6%), diarrhea (26.5%), and pruritus (24.5%). Grade 2 and 3, transient, non-serious, elevations of liver function tests (LFTs) were observed in 15 patients with the majority being completely asymptomatic. Of these patients, 11 underwent drug interruptions, and 6 of 7 patients were successfully rechallenged and returned to treatment with no recurring Grade 3 or higher LFT elevations. Nine SAEs were reported in the study, with all except one unrelated to galeterone. The single, related, grade 4 case involved rhabdomyolysis that occurred in the setting of simvastatin therapy (40 mg qd) and underlying renal insufficiency. No events of adrenal mineralocorticoid excess (AME) were observed in this study. PSA reductions were seen in a majority of patients; 24 (49%) patients had >30% maximal PSA reductions, including 11 patients (22%) with >50% maximal PSA reductions.
Conclusion: Galeterone was well tolerated, with all cohorts showing an acceptable safety profile. Galeterone also demonstrated activity in patients with CRPC. Additional long term safety will be further explored in a planned phase II study.