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Custirsen fails to improve survival in castration-resistant prostate cancer
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COPENHAGEN, Denmark — The addition of custirsen to cabazitaxel and prednisone did not significantly extended OS in previously treated patients with metastatic, castration-resistant prostate cancer, according to results of the randomized controlled phase 3 AFFINITY trial presented at the European Society for Medical Oncology Congress.
“Hormonal therapy works very nicely in almost all men who suffer from this disease, but not necessarily for very long,” Karim Fizazi, MD, PhD, head of the department of cancer medicine at the Institut Gustave Roussy in Villejuif, France, said during a press conference. “Until recently, we haven’t had many options to offer to these patients. In the last 5 years, a series of compounds have shown to increase OS in castration-resistant prostate cancer. However, none of these compounds can achieve a cure in patients with metastatic disease, so we still need more treatment, and treatment that can reverse or prevent resistance to these drugs.”
Clusterin is a cytoprotective protein that is expressed after exposure to hormone therapy or chemotherapy, allowing cancer cells to survive and reducing the efficacy of treatment.
Custirsen (OGX-011, OncoGenex Pharmaceuticals) has been shown in in vitro and animal models to block production of clusterin. Further, a randomized phase 2 trial suggested that the addition of custirsen to chemotherapy improved outcomes, with approximately a 40% reduction in the risk for death of castration-resistant prostate cancer.
Fizazi and colleagues evaluated whether the addition of custirsen to chemotherapy would improve OS in a phase 3 trial of 635 men (median age, 68 years) with castration-resistant prostate cancer who had progressed after docetaxel. Fifty percent of patients had a Karnofsky score of 80% of lower.
Researchers randomly assigned patients to receive 25 mg/m2 IV cabazitaxel on day 1 with 10 mg prednisone alone or with 640 mg IV custirsen on days 1, 8 and 15. Patients received treatment until disease progression, unacceptable toxicity or receipt of 10 cycles.
OS served as the primary endpoint.
In the intent-to-treat population, custirsen did not improve survival compared with standard chemotherapy (median OS, 14.2 months vs. 13.4 months; HR = 0.94; 95% CI, 0.79-1.12).
Among 392 men who met criteria for poor prognosis, OS also did not significantly differ between the arms (median OS, 11.1 months vs. 10.9 months; HR = 0.91; 95% CI, 0.72-1.15).
Researchers conducted analyses to evaluate how treatment impacted the expression of clusterin.
“We tried to look at what happened to serum clusterin to find out if clusterin is not a good enough target, or if the drug is not good enough to target clusterin,” Fizazi said.
In the control arm, outcomes did not differ among patients, regardless of how serum clusterin changed. However, in patients in the experimental arm, those who achieved a decline in serum clusterin while on treatment with custirsen demonstrated better outcomes compared with patients who did not demonstrate clusterin declines.
“Perhaps the drug is not potent enough to have this effect translated into an OS improvement,” Fizazi said.
Discontinuation due to progressive disease occurred in 28.9% of patients treated with custirsen and 25% of patients treated with chemotherapy, and 21.9% of patients treated with custirsen vs. 18.9% of patients treated with chemotherapy discontinued due to adverse events. The incidence of grade 3 or worse adverse events (75.9% vs. 66.3%) and serious adverse events (49.2% vs. 42.3%) appeared comparable between the arms.
“One conclusion from this study involves the prerequirement that we need for the future when designing new phase 3 trials,” Fizazi said. “We had a strong biological rationale and a strong clinical signal, because OS was improved in the randomized phase 2 trial. But, we didn’t really select all the patients based on a biomarker. This is what we need to achieve now for future development in prostate cancer.”– by Alexandra Todak
Reference:
Fizazi K, et al. Abstract LBA9_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: The study was funded by OncoGenex Pharmaceuticals. Fizazi reports advisory board roles with and honoraria from Amgen, Astellas, Bayer, Genentech, Janssen, Orion, Sanofi and Takeda. Please see the abstract for a list of all other researchers’ relevant financial disclosures.