A phase III randomized controlled trial of custirsen in combination with cabazitaxel and prednisone in patients with previously treated metastatic, castration-resistant prostate cancer (mCRPC) failed to show a significant survival gain over cabazitaxel and prednisone alone. Also in the subgroup of patients with a poor prognosis, no overall survival (OS) benefit was seen with custirsen.1
Treatment failure is the major barrier in extending survival in patients with advanced cancer. Clusterin is a cytoprotective protein that is upregulated by chemotherapy in cancer cells. It is known to be involved in carcinogenesis and tumour growth and also plays a role in the development of treatment resistance. Custirsen blocks the production of clusterin and in a phase II trial, evaluating a combination of custirsen with chemotherapy in men with mCRPC, custirsen was associated with improved outcomes.2 In addition to this, an earlier phase III trial of custirsen in combination with docetaxel suggested that patients with more aggressive cancers derived clinical benefit from this combination.3
In the AFFINITY trial, 635 patients with mCRPC, who had previously been treated with docetaxel, were randomized to 21-day cycles of custirsen (640 mg IV, 3 loading doses days -9 to -1, then weekly) plus cabazitaxel (25 mg/m2 IV) and prednisone (10 mg/day) or cabazitaxel and prednisone plus placebo. Patients in the trial were treated until disease progression, unacceptable toxicity, or until ten treatment cycles were completed. The primary endpoint of the study was overall survival.
The median OS in the custirsen arm was reported to be 14.2 months, which was not significantly longer than the 13.4 months median OS observed in the placebo arm (HR[95%CI]: 0.945[0.796-1.124]; p=0.529). The same was observed in the 62% of patients who met the criteria for poor prognosis. In this subgroup, the median OS was 11.1 months with custirsen compare to 10.9 months in the placebo group (HR[95%CI]: 0.918[0.727-1.158]; p=0.470).1
Similar numbers of patients in each arm discontinued their treatment due to progressive disease: 28.9% in the custirsen arm and 25% in the placebo arm. Slightly more patients in the custirsen arm discontinued therapy due to adverse events (21.9% vs. 18.9% in the placebo arm). The most frequently reported serious adverse events were neutropaenia, anaemia, fatigue, asthenia, bone pain, and febrile neutropaenia.1
In summary, despite the strong rationale for adding custirsen to chemotherapy to overcome resistance in mCRPC, the phase III AFFINITY trial did not meet its primary endpoint of an improved OS. One possible explanation for the failure of this trial could be that custirsen is not potent enough to adequately lower the clusterin levels in patients. This hypothesis is supported by the observed correlation between a more pronounced reduction in clusterin levels and a better OS.
- Fizazi K, Hotte S, Saad F, et al. Final overall survival (OS) from the AFFINITY phase 3 trial of custirsen and cabazitaxel/prednisone in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). Presented at ESMO 2016; Abtract LBA9_PR
- Saad F, Hotte S, North S et al. Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c. Clin Cancer Res 2011;17:5765-73.
- Chi KN, Higano CS, Blumenstein BA, et al. Phase III SYNERGY trial: Docetaxel +/- custirsen and overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and poor prognosis. J Clin Oncol 2015;33 (suppl; abstr 5009).