CHICAGO – An experimental therapy is closing in on a new target in metastatic castration-resistant prostate cancer: heat shock protein 27.
OGX-427 is a second-generation antisense oligonucleotide that is designed to reduce production of heat shock protein 27 (Hsp27), a cell-survival protein that is highly expressed in many cancers including prostate and associated with poorer prognosis. Hsp27 increases after castration therapy as a stress survival response and has been shown to be highly overexpressed in castration-resistant prostate cancer tissues, Dr. Kim N. Chi explained at the annual meeting of the American Society of Clinical Oncology.
Dr. Kim N. Chi
In phase I studies, OGX-427 decreased tumor markers in patients with prostate and ovarian cancer and measurable disease by more than 15% in roughly one-third of patients. The drug has a prolonged half-life of about 10 days, but no dose-limiting toxicities were identified. Mostly the adverse events were dose-dependent, grade 1-2 infusion reactions, said Dr. Chi, chair of the genitourinary group and medical director of clinical trials at the Vancouver (British Columbia) Prostate Centre–BC Cancer Agency.
The goal of the current phase II trial was to improve the 12-week progression-free rate in chemotherapy naive men with metastatic castration-resistant prostate cancer. Patients were randomized to twice-daily prednisone 5 mg alone or with OGX-427 600 mg IV in three loading doses in the first week followed by 1,000 mg weekly for up to 24 weeks for patients with a best response of stable disease or continuously for responders.
The current analysis includes 42 of the 72 planned patients. Because of the frequent use of corticosteroids to manage infusion reactions, the control arm was added to isolate out the effect of OGX-427, he said.
The 22 patients in the OGX-427 arm were slightly younger than the 20 controls were (median 66 years vs. 72 years), but the OGX-427 arm had more patients with lung metastases (14% vs. 0%), elevated lactate dehydrogenase (36% vs. 15), elevated alkaline phosphatase (32% vs. 10%), prior prednisone therapy (23% vs. 15%) and 5 or more circulating tumor cells/7.5 mL of blood (96% vs. 90%), Dr. Chi pointed out.
Median treatment duration was 24 weeks with OGX-427 and 14 weeks with prednisone alone. In all, 93% of controls came off treatment because of disease progression vs. only 31% on OGX-427, although 25% also did so because of adverse events.
At 12 weeks, 71% of patients on OGX-427 were progression free, compared with 40% on prednisone alone, he said.
A prostate-specific antigen decline of 50% or more occurred in 50% and 20%, respectively.
The objective response rate was 44%, including one complete response and three partial responses, among nine evaluable OGX-427 patients vs. 0% among 12 evaluable controls.
Sixty percent of OGX-427 patients have had either a decrease of more than 5 circulating tumor cells/7.5 mL or maintained a less 5 cell/7.5 mL count, compared with 41% of controls having a similar decline.
Treatment-related events have been predominantly infusion related and were described as a flulike illness that occurs mainly in the first couple of infusions and includes grade 1/2 chills (55%), diarrhea (41%), nausea (32%), flushing (23%), vomiting (23%) and pyrexia (18%).
"Patients tend to build tolerance and they [events] are brief and self-limited," Dr. Chi said.
Dr. Karim Fizazi
Grade 3/4 lymphopenia was more common with OGX-427 at 18% vs. 10% among controls but did not result in any infectious sequelae.
"These preliminary data identify Hsp27 as a novel therapeutic target and supports continued evaluation of OGX-427 for patients with castration-resistant prostate cancer," he concluded.
Discussant Dr. Karim Fizazi, with Institut Gustave Roussy, Villejuif, France, said he was surprised by the "quite-high" adverse event rates for chills, nausea, and diarrhea, but that fortunately they were mostly grade 1 and 2. He said the biological background for targeting Hsp27 is very strong and called the preliminary evidence of clinical activity exciting.
"If these data are confirmed, which I don’t really doubt they will, what will be the phase III development path for such IV [intravenous] weekly drug infusions in the context of all the drugs we now have in prostate cancer?" he asked.
The current trial is ongoing, with a phase II trial of OGX-427 plus abiraterone (Zytiga) in castration-resistant prostate cancer to be initiated later this year, according to OncoGenex Pharmaceuticals. The company is also developing the targeted anticlusterin molecule OGX-001 to be evaluated later this year in two phase III trials in castration-resistant disease.
Dr. Chi reports research funding from OncoGenex Pharmaceuticals, which is developing OGX-427. Dr. Fizazi reports a consultant or advisory role with OncoGenex and Exelixis.