Heat-Shock Protein Inhibitor Delays Disease Progression in Phase II Trial

Kim Chi, MD

The novel agent OGX-427, which targets heat-shock protein 27 (Hsp27), delayed disease progression in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC), according to the preliminary results of a phase II study presented at ASCO 2012.

“These preliminary data identify Hsp27 as a novel therapeutic target and support continued evaluation of OGX-427 for patients with castration-resistant prostate cancer,” said the study’s primary investigator, Kim Chi, MD, BC Cancer Agency, British Columbia, Canada, in a presentation at ASCO.

Known as a “cell-survival” protein, Hsp27 inhibits apoptosis, or programmed cell death, in tumors and is associated with treatment resistance. “Hsp27 is highly expressed in many cancers, including prostate, and high expression has been correlated with poor prognosis,” said Chi. “[Its levels] also increase after castration therapy as a stress survival response, and it is shown to be highly overexpressed in castration-resistant metastatic prostate cancer tissues,” he added.

In the early data from their ongoing phase II trial, Chi et al randomized 42 patients with mCRPC 1:1 to either OGX-427 (600 mg IV x 3 loading doses, week 1; 1000 mg IV weekly x 24 weeks; n = 22) plus prednisone (5 mg twice daily) versus prednisone alone (5 mg twice daily; n = 20). The primary endpoint was the proportion of patients who were progressionfree at 12 weeks.

Baseline characteristics for the OGX-427 treatment group included a median age of 66 years and a median prostate-specific antigen (PSA) level of 66, with all patients having an ECOG Performance Status of 0 or 1, and 73%, 45%, and 14%, of patients having metastases in the bone, lymph nodes, and lungs, respectively. Twelve patients in the OGX-427 arm had Gleason scores >7, nine had Gleason scores ≤7, and one patient’s score was not recorded.

At 12 weeks, 71% of patients in the OGX-427 arm did not have disease progression, as compared with 40% of the patients receiving prednisone alone. Additionally, half of the patients receiving OGX-427 had PSA declines ≥50% as compared with 20% in the control group. Reductions in circulating tumor cell levels, as well as partial and complete response rates, were also higher in the OGX-427 arm.

Ten patients from the control group crossed over to the treatment arm at progression. Although it is still early, there has been a partial response as well as PSA declines observed in these patients, according to Chi.

In terms of toxicity, “Treatment-related adverse events have been predominantly infusion-related, grade 1 and 2, and manageable,” Chi said. The infusion reaction mainly occurs with the first few infusions and includes chills, diarrhea, nausea, flushing, vomiting, and pyrexia. “Patients tend to build tolerance and the events are usually brief and self-limited,” Chi noted.

Grade 3-4 adverse events in the treatment group included lymphopenia in four patients and hyperglycemia in three patients.

Earlier this year, OncoGenex announced plans for an investigator-initiated phase II trial that would examine combination therapy with OGX-427 and abiraterone acetate (Zytiga) in patients with mCRPC.

Ongoing clinical trials are also investigating OGX- 427 in bladder cancer.

Chi KN, Hotte SJ, Ellard S, et al. A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC). J Clin Oncol. 2012;30(suppl; abstr 4514).