Combination Therapy for Docetaxel-Pretreated Metastatic Castration-Resistant Prostate Cancer


Key Points

  • Among patients with metastatic prostate cancer previously treated with docetaxel, the addition of custirsen to cabazitaxel/prednisone did not improve overall survival.
  • No survival benefit was observed among high-risk patents.

The phase III AFFINITY trial has shown no survival benefit with the addition of the antisense oligonucleotide custirsen to cabazitaxel (Jevtana)/prednisone in patients with metastatic prostate cancer previously treated with docetaxel. These findings were reported in The Lancet Oncology by Beer et al. Custirsen inhibits the production of clusterin, an antiapoptotic protein upregulated in response to chemotherapy that confers treatment resistance.

Study Details

In the open-label trial, 635 men from 95 sites in 8 countries were randomized between September 2012 and September 2014 to receive cabazitaxel at 25 mg/m² every 21 days plus oral prednisone at 10 mg daily with (n = 317) or without (n = 318) custirsen at 640 mg intravenously on days 1, 8, and 15 plus three previous loading doses until disease progression, unacceptable toxicity, or completion of 10 treatment cycles. Randomization was stratified by opioid use for prostate cancer–related pain at screening, disease progression following first-line docetaxel, and previous treatment with abiraterone (Zytiga) or enzalutamide (Xtandi). The co-primary endpoints were overall survival in all patients and in a poor-prognosis subgroup (195 in the custirsen group, 197 in the control group); the poor-prognosis group included patients meeting at least two of the following criteria: Karnofsky performance status ≤ 80%, liver metastasis, lactate dehydrogenase concentration ≥ 360 U/L or higher, hemoglobin ≤ 120 g/L, and prostate-specific antigen ≥ 150 μg/L.

Overall Survival

Median follow up was 28.3 months in the custirsen group and 29.8 months in the control group. Median overall survival was 14.1 vs 13.4 months (hazard ratio [HR] = 0.95, P = .53) among all patients and 11.0 vs 10.9 months (HR = 0.97, P = .80) among high-risk patients.

Adverse Events

The most common grade ≥ 3 adverse events in the custirsen vs control groups were neutropenia (22% vs 20%), anemia (22% vs 16%), fatigue (7% vs 6%), asthenia (5% vs 3%), bone pain (5% vs 2%), and febrile neutropenia (5% vs 3%). Serious adverse events occurred in 49% vs 42% of patients. Death occurred within 30 days of treatment in 27 patients in the custirsen group, with 7 considered related to treatment, and in 17 patients in the control group, with 8 considered related to treatment.

The investigators concluded: “We noted no survival benefit in men with metastatic castration-resistant prostate cancer with the addition of custirsen to cabazitaxel and prednisone treatment. Cabazitaxel and prednisone remains the standard of care for patients with metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy.”

The study was funded by OncoGenex Pharmaceuticals.

Tomasz M. Beer, MD, of the Oregon Health and Science University Knight Cancer Institute, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.