Custirsen Combination Misses Goal in Phase III mCRPC Trial

Silas Inman
Published Online: Monday, April 28, 2014
Scott Cormack, CEO and President

Scott Cormack, President & CEO

The combination of custirsen (OGX-011) with docetaxel and prednisone failed to significantly extend survival as a first-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC), according to top-line results from the phase III SYNERGY study released by the companies developing the drug, Teva and OncoGenex.

In the SYNERGY trial, 1022 men with mCRPC were randomized to receive first-line treatment with standard docetaxel and prednisone with or without custirsen at 640 mg weekly. The median overall survival (OS) was 23.4 months with the addition of custirsen compared to 22.2 months with docetaxel plus prednisone alone (hazard ratio [HR] = 0.93; P = .207). Side effects were consistent with phase II findings, which included febrile neutropenia, fever, pleural effusion, and dyspnea. Full data, including the secondary endpoint of progression-free survival (PFS), will be submitted for presentation later this year.

"The results of SYNERGY are unexpected, particularly given the wealth of scientific evidence supporting the targeting of clusterin to combat treatment resistance in first-line prostate cancer," Scott Cormack, president and CEO of OncoGenex, said in a release. "A thorough analysis of the data is underway to understand the potential factors that may have contributed to the results."

Custirsen is a second-generation antisense oligonucleotide designed to inhibit production of the stress-induced cytoprotective chaperone clusterin. Earlier studies found that elevated levels of clusterin were associated with advanced tumor stage, metastasis, treatment resistance, and adverse outcomes in several types of cancer. In these studies, the combination of custirsen with prednisone and chemotherapy was shown to significantly lower clusterin levels, resulting in an extension in survival for men with mCRPC.

In the phase II study, 82 patients with mCRPC were randomized 1:1 to receive docetaxel and prednisone with or without custirsen. The median OS was 23.8 months with custirsen compared with 16.9 months without. The median PFS with custirsen was 7.3 months versus 6.1 months without.

Results from the phase II study were published in the Journal of Clinical Oncology in August 2010. At this time, the phase III SYNERGY study was also initiated. However, since 2010, the treatment landscape for patients with CRPC has drastically changed, with the approval of new drugs including abiraterone acetate, enzalutamide, and radium-223.

“We are disappointed with these results," Michael Hayden, MD, president of global R&D and chief scientific officer at Teva Pharmaceutical Industries Ltd, said in a release. "Addressing treatment resistance is critical in the fight against cancer. We are working with OncoGenex to more fully understand these data.”

In addition to the SYNERGY trial, custirsen is also being explored in the phase III AFFINITY trial in combination with cabazitaxel plus prednisone as a second-line treatment for men with mCRPC. This trial is expected to finish enrolling approximately 630 men in the second half of 2014. On April 23, 2014, the FDA granted a Fast Track designation to custirsen plus cabazitaxel with prednisone, based on the AFFINITY trial. In 2012, custirsen in combination with docetaxel also received a Fast Track designation, based on the SYNERGY trial.

"[W]e remain strong in our belief that targeting mechanisms of treatment resistance is a critical path forward in the fight against cancer and we continue to actively pursue this approach," Cormack said in a release. "We would like to thank the men who participated in the SYNERGY trial and the friends and families who supported them." 

Custirsen is also being explored in combination with second-line docetaxel as a treatment for patients with locally advanced or metastatic non-small cell lung cancer. The phase III study, known as ENSPIRIT, hopes to enroll 1100 patients with a primary endpoint of OS.

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