Novel Agent Could Help Men with Metastatic CRPC

Kim Chi, MD
Kim Chi, MD

CHICAGO—Men with metastatic castration-resistant prostate cancer (CRPC) may benefit from treatment with OGX-427, an investigational drug that inhibits production of a protein implicated in cancer progression.

Overexpression of the protein, Heat Shock Protein 27 (Hsp27), is thought to be an important factor leading to the development of treatment resistance and is associated with negative clinical outcomes in patients with various tumor types. Hsp27 is involved in multiple cancer cell survival and growth pathways implicated in progression. In particular for prostate cancer, Hsp27 forms complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes in prostate cancer models. OGX-427 is a second generation antisense oligonucleotide that inhibits Hsp27 expression.

“No agent like this has before shown this kind of activity,” said study investigator Kim Chi, MD, a medical oncologist at BC Cancer Agency in British Columbia.

OGX-427 has been shown to be well tolerated with single-agent activity in phase 1 studies.

In this current study, which was presented at the American Society of Clinical Oncology 2012 annual meeting, chemotherapy-naïve patients with no or minimal symptoms were randomized to receive three loading doses of OGX-427 600 mg IV then 1000 mg IV weekly with prednisone 5 mg twice a day or prednisone only. The primary endpoint was the proportion of patients who were progression free at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA decline, measurable disease response, and changes in circulating tumor cell (CTC) numbers.

Sixty-four patients have been randomized and results from 42 patients in the first stage were analyzed (22 on OGX-427 plus prednisone, 20 on prednisone alone). At week 12, 71% of patients in the OGX-427 plus prednisone group were progression free compared with 40% in the prednisone-only arm.

A 50% or greater PSA decline occurred in 50% of patients on OGX-427 plus prednisone versus 20% of patients treated with prednisone alone. The investigators observed measurable disease response in 44% of patients on OGX-427 plus prednisone, including one complete response and three partial responses, compared with none of the patients on prednisone alone.

In addition, 55% of the combination arm versus 41% of the prednisone-only arm experienced a decrease in CTCs from five or more cells per 7.5 mL to less than five cells per 7.5 mL.

OGX-427 appeared to be well-tolerated. “The patients get an almost flu-like syndrome, but it is self-limiting,” Dr. Chi said. “It usually involves chills, diarrhea, nausea, flushing, vomiting and high fever in about 50% of patients, but 50% have had no or minimal side effects.”

Adverse events (AEs) were mainly grade 1/2 OGX-427 infusion reactions. However, there were three grade 4 AEs: hemolytic uremic syndrome, a pulmonary embolus, and dizziness. 

Mark Garzotto, MD, Associate Professor of Urology and Radiation Medicine at Oregon Health & Science University in Portland, said if studies continue to go well, OGX-427 could be an important new agent for a significant number of PCa patients.

“If these data mature, this would open up a novel approach for the treatment of a variety of cancers,” Dr. Garzotto said. “Targeting Hsp27 is an alternate and novel way of attacking the AR, which is critically important for prostate cancer recurrence and progression after castration. However, there are several drugs which are currently available or in development for targeting the AR in castration-resistant prostate cancer. If this drug becomes available we will have to develop new decision pathways for choosing the optimal AR targeting method.”

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