CHICAGO—A new compound that specifically inhibits production of the cell-survival protein clusterin appears to be well tolerated and produces PSA responses when given in combination with docetaxel and prednisone in men with metastatic hormone refractory prostate cancer (HRPC), a study found.


Clusterin production is associated with treatment resistance in many cancers and increases in response to various cancer treatments, including hormone ablation therapy, chemotherapy, and radiation therapy.

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Preclinical studies have shown that inhibition of clusterin can disable the tumor cell’s adaptive defenses, rendering the tumor cells susceptible to attack with a variety of cancer therapies. Clusterin is also associated with androgen independent progression and it is overexpressed in HRPC.


OGX-011, developed by OncoGenex Technologies/Isis Pharmaceuticals, inhibits clusterin expression in humans and potentiates chemotherapy activity in prostate xenografts. In a phase II study, 81 patients with metastatic or locally recurrent prostate cancer refractory to hormone therapy were randomized to one of two treatment arms to receive either 640 mg OGX-011 per week given IV in combination with docetaxel and prednisone, or docetaxel plus prednisone. Patients were followed for a minimum of 4.8 months. The mean age of the patients was 67 years (range: 49-84).


The median progression-free survival was 7.3 months in the men in the OGX-011 arm compared with 5.8 months in patients in the other arm. In addition, disease progression occurred in fewer patients who received OGX-011 plus docetaxel.


The progressive measurable disease as the best response occurred in 4% of the patients on the study drug and in 22% of the patients in the docetaxel plus prednisone only arm. Study findings were presented here at the annual meeting of the American Society of Clinical Oncology.


PSA progression as the best response occurred in no patients in the OGX-011 plus docetaxel arm and in 10% of patients in the docetaxel arm. Although response rates for both measurable disease and PSA assessments in the study arms were similar, disease stabilization by both assessments occurred in more patients in the OGX-011 arm. The primary end point of PSA response was seen in 20 of 40 patients who received OGX-011.


The median number of cycles of chemotherapy administered was eight in patients who received OGX-011 plus docetaxel (range: 1-10) and six in patients with received docetaxel plus prednisone (range: 1-10).


“I think we can say this agent is promising,” said lead investigator Kim Chi, MD, a medical oncologist at the Vancouver Prostate Cancer and an assistant professor of medical oncology at the BC Cancer Agency in Vancouver. “The data on the duration of time to progression, the tolerability of the treatment, and the depth of PSA responses were all good.”

The agent may offer new hope in this patient population because of its unique mechanism of action, he said. “This agent inhibits the expression of clusterin and by doing this it decreases the resistance of prostate cancer cells and thereby enhanced the efficacy of docetaxel in preclinical models,” Dr. Chi said. This is really the first study to look at this agent in this patient population so we don’t know yet if it works differently in early stage patients.”


The following adverse events (all grade 1 or 2) were documented more commonly in patients given OGX-011 than patients in the other arm: fever (50% vs. 15%), rigors/chills (60% vs. 7%), sweating (25% vs. 12%), sensory neuropathy (70% vs. 49%), and limb edema (38% vs. 27%).


The majority of patients experienced granulocytopenia and neutropenia, with similar frequency and magnitude in each arm. Grade 3 or 4 lymphopenia was more common in patients receiving OGX-011 (53%) than in patients in the other arm (20%). There were 11 serious adverse events reported for each study arm.