Custirsen Combo Falls Short in Phase III mCRPC Trial

Scott Cormack

Adding custirsen to cabazitaxel (Jevtana) and prednisone in the second-line setting failed to improve overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) in the phase III AFFINITY trial, according to OncoGenex, the company developing the drug.

The open-label AFFINITY trial included 634 men with mCRPC who progressed on docetaxel. Patients were randomized to cabazitaxel plus prednisone with or without weekly custirsen. Treatment was administered until progression, unacceptable toxicity, or the completion of 10 cycles. The study was conducted at 95 locations in North America, Europe, Russia, and Australia.

“We are obviously disappointed that custirsen was unable to demonstrate a survival benefit in prostate cancer. We would like to thank the patients who participated in the AFFINITY trial and their caregivers, as well as the investigators and their teams for their commitment to improving cancer care for patients who are in desperate need of new treatment options,” Scott Cormack, president and CEO of OncoGenex, said in a statement.

The safety profile for custirsen in the AFFINITY trial was similar to adverse-event reports in prior studies of the drug in mCRPC. OncoGenex plans to submit the full study data for presentation as a late-breaking abstract at the 2016 ESMO Annual Congress in October.

OncoGenex also announced its intention to begin communication with the FDA to assess the potential for an early analysis of the ongoing international, open-label phase III ENSPIRIT study (NCT01630733). That trial is evaluating the potential of custirsen plus docetaxel as a second-line regimen for patients with non—small cell lung cancer. The randomized study has a targeted enrollment of 700 patients and is being conducted at 50 locations globally.

“Given that the ENSPIRIT trial has nearly completed enrollment and we believe there are likely a sufficient number of events to determine the effect of custirsen in NSCLC, we are eager to expedite the final data analysis, which would allow us to conserve resources and fully understand the value of the asset as we evaluate our alternatives to maximize shareholder value,” said Cormack.

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.

OncoGenex announced in April 2014 that in the phase III SYNERGY trial, the combination of custirsen with docetaxel and prednisone failed to significantly improve OS as a first-line treatment for men with mCRPC.

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 (HR, 0.93; P = .207). Side effects were consistent with phase II findings, which included febrile neutropenia, fever, pleural effusion, and dyspnea.

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 (Zytiga), enzalutamide (Xtandi), and radium-223 (Xofigo).