Overall Survival Not Improved With Custirsen For Castration-Resistant Prostate Cancer

The addition of custirsen to docetaxel and prednisone is not beneficial in metastatic castration-resistant prostate cancer

medwireNews: Negative results have been published for the SYNERGY trial of the clusterin inhibitor custirsen, used in combination with docetaxel and prednisone, for patients with metastatic castration-resistant prostate cancer.

As reported in The Lancet Oncology, the phase III study did not show an overall survival (OS) gain with the second-generation antisense oligonucleotide against the chaperone protein clusterin, associated with treatment resistance.

OS was comparable in the 510 patients randomly assigned to receive three loadings doses of custirsen 640 mg followed by the same dose weekly alongside docetaxel plus prednisone and the 512 patients given docetaxel and prednisone only, at a median of 23.4 versus 22.0 months.

Kim Chi, from the University of British Columbia in Vancouver, Canada, and co-authors say the custirsen regimen was “reasonably well tolerated”, although at least one serious adverse event occurred in 43% of 501 patients in the custirsen group safety analysis and 36% of the 499 controls. The rates of adverse event-related deaths were 5% in both groups.

The most common adverse events in the custirsen and controls groups were grade 3 (13 vs 6%) and grade 4 (20 vs 15%) neutropenia, grade 3 (10 vs 6%) and grade 4 (1 vs <1%) febrile neutropenia, and grade 3 (11 vs 8%) and grade 4 (1 vs <1%) fatigue.

“Further insights into identification of patients who could potentially benefit from custirsen therapy will emerge from phase 3 studies of custirsen with cabazitaxel in patients with metastatic castration-resistant prostate cancer and an ongoing study in patients with non-small cell lung cancer receiving second-line chemotherapy”, the authors conclude.

The US authors of a linked comment note that the SYNERGY trial “joins a long list of phase 3 trials that have failed to show improved outcomes when adding a biological agent to docetaxel and prednisone”.

Guru Sonpavde, from the University of Alabama at Birmingham, and Andrew Armstrong, from Duke Cancer Institute in Durham, North Carolina, say it is “noteworthy” that the phase II trial before SYNERGY had demonstrated a RECIST objective response for the custirsen combination of 19% versus 25% with docetaxel and prednisone alone.

“Thus, assigning a higher value to differences in objective response might have led to a decision to abandon phase 3 investigation”, they suggest.

The commentators conclude: “Paying greater attention to objective responses and their durability could be more important when investigating non-cytotoxic biological and immunotherapeutic agents.

“Although powering a phase 2 trial to measure objective responses might prolong the accrual period modestly, this delay could be a smaller price to pay than the price of a large, negative, phase 3 trial.” 


Chi KN, Higano CS, Blumenstein B, et al. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol; Advance online publication 7 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30168-7

Sonpavde G, Armstrong AJ. Drug development in prostate cancer: time to embrace RECIST? Lancet Oncol; Advance online publication 7 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30149-3

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