Last October at the European Cancer Congress 2013 there was a release of data from a phase 3 study of Ipilimumab (CA 184-043) that showed that it might be effective in treating castration-resistant prostate cancer in men who have a low burden of disease; however it failed to show at the required 95% confidence level required for FDA approval that it was a generally effective treatment for prostate cancer.

Ipilimumab (Ipi or Yervoy) is already approved and commonly used for the treatment of Melanoma. Ipi is an immune therapy that differs in its mode of action from the already approved immunologic therapy Provenge (approved for the treatment of prostate cancer). Provenge sensitizes the immune system to fight prostate cancer by training the immune system to recognize cancer cells while Ipi removes the breaks on the immune system allowing it to generally attack the cancer.

The reported data was derived from the CA 184-043 trial, a Phase 3, multicenter, randomized, double blind trial of 799 men with castration-resistant prostate cancer treated with ipilimumab or placebo after docetaxel and a single radiation dose (8 Gy).  The subject men had to have one or more symptomatic bone metastases that could be irradiated with a single dose of radiotherapy (8 Gy).

After the irradiation, 399 of the men were randomized to receive ipilimumab at an intravenously infused dose of 10 mg/kg on weeks 1, 4, 7 and 10, and then every 12 weeks until progression or intolerable toxicity.  Four hundred (400) men were also randomized to receive a matching placebo.

An actual review of the final data showed a failure:

1-    Median overall survival was 11.2 months in men treated with ipilimumab and 10 months for men in the placebo group (hazard ratio

[HR] = 0.85, P = .0053)

2-  Overall survival rates of 47% and 40% at 1 year, and 26% and 15% at 2 years.


However, a break down of the data into subgroups tells a different story and a more interesting story.

In men whose disease progressed within 6 months of having chemotherapy (docetaxel), the primary endpoint of overall survival just missed reaching statistical significance in the CA184-043 trial at a median of 11.2 months in men treated with Ipi and of 10 months for those given placebo (hazard ratio [HR] = 0.85, P = .0053).

Overall survival at 1 year was 47% and 40% in each group, respectively, and 26% and 15% at 2 years.

Men without visceral metastases were more likely to benefit than were those with visceral metastases, reported Dr. Winald Gerritsen of Radboud University Medical Center in Nijmegen, the Netherlands. The HR for overall survival according to the absence or presence of visceral metastases was 0.73.

They also reported that the overall survival was better with Ipi in men with an ECOG performance status of 0 rather than 1 (HR = 0.72), alkaline phosphatase levels less than 1.5 times the upper limit of normal rather than higher (HR = 0.78), hemoglobin levels of 11 g/dL rather than lower values (0.79), and normal rather than elevated lactate dehydrogenase levels (HR = 0.82).

In other words analysis showed a greater overall survival benefit for immunotherapy with Ipi in men with a better prognostic profile, based on alkaline phosphatase level, hemoglobin level, and the absence of visceral metastases. Overall survival was 22.7 months in these men and 15.8 months for men in the placebo group (HR = 0.62).  This translates into a better survival advantage for men at an earlier disease stage, not dissimilar to our findings with Provenge.

Progression-free survival was also significantly improved at 4 months for ipilimumab therapy and 3 months for placebo (HR = 0.70; P less than .0001). Further, a higher percentage of men had a prostate-specific antigen response if they were given the immunotherapy with Ipi (13.1% vs. 5.3%).

Unfortunately, this really should not have come as a surprise. Immune therapy belongs in the early disease stages and needs to be evaluated at earlier disease stages.  Why would there be any difference with Ipi? Why did we lose this drug, or at least delay its availability to men with prostate cancer given our universal understanding about using immune therapy in earlier disease stages. Why was Ipi tested in the post-chemotherapy stage of the disease?

We should be using the knowledge we already have and make better trials that will reflect what we know.  If we have a reasonable belief that a drug will be more effective at a certain disease stage lets test it there and then worry about evaluating it at other disease stages.

Does this make sense, what do you think?

Joel T. Nowak, M.A., M.S.W.