Ipilimumab fails to show overall survival benefit in mCRPC after chemotherapy


According to a media release issued by Bristol-Myers Squibb this morning, the company’s recombinant, human, monoclonal antibody ipilimumab (Yervoy) — which acts by blocking the effects of cytotoxic T- lymphocyte antigen-4 (CTLA-4) — has shown no overall survival benefit in treatment of men with chemotherapy-refractory, metastatic, castration-resistant prostate cancer (mCRPC).

The randomized, double-blind Phase III clinical trial (Study 043) had been designed to compare the effects of ipilimumab to a placebo after radiation therapy in men with advanced mCRPC who had already received treatment with docetaxel.

According to the media release:

  • The trial enrolled a total of 799 patients.
    • 399 patients were randomized to treatment with ipilimumab.
    • 400 patients were randomized to treatment with a placebo.
  • Median overall survival (OS) times were
    • 11.2 months for patients treated with ipilimumab.
    • 10 months for patients treated with a placebo.
  • The difference in OS for patients in the two arms of the trial (1.2 months or about 6 weeks) was not statistically significant (hazard ratio [HR] = 0.85).
  • Survival rate data showed that
    • 47 percent of patients treated with ipilimumab were still alive at 1 year after initiation of treatment.
    • 40 percent of patients treated with a placebo were still alive at 1 year after initiation of treatment.
    • 26 percent of patients treated with ipilimumab were still alive at 2 years after initiation of treatment.
    • 15 percent of patients treated with a placebo were still alive at 2 years after initiation of treatment..
  • Median progression-free survival data showed that ipilimumab had greater activity than a placebo (HR = 0.70)
  • Data on the reduction in PSA levels to less than 50 percent of the baseline levels showed that
    • 13.1 percent of patients treated with ipilimumab had this degree of PSA reduction.
    • 5.3 percent of patients treated with a placebo had this level of PSA reduction.
  • Pre-specified subset analyses suggest that Yervoy may be more active in patients with indicators for less advanced disease.
  • Treatment-related adverse events were common, and most were immune-related.
    • Immune-related gastrointestinal adverse effects of Grade  3 or higher were reported in 18 percent of ipilimumab patients (as compared to 1 percent of palecbo patients).
    • Immune-related adverse effects on liver function of Grade 3 or higher were reported in 5 percent of ipilimumab patients (as compared to 1 percent of placebo patients).
    • Adverse effects on endocrine function of Grade 3 or higher were reported in 2 percent of ipilimumab patients (as compared to 1 percent of placebo patients).
    • Adverse dermatologic effects of Grade 3 or higher were reported in 1 percent of ipilimumab patients (as compared to 0 percent of placebo patients).
    • The incidence of drug-related death and GI perforation was 1 percent in patients treated with ipilimumab (as compared to 0.5 percent of placebo patients).

The company states that these data will be presented at the 2013 European Cancer Congress in an oral session on September 28 this year (abstract no. 2850).

Clearly these data will be a disappointment to the developer. However, The “New” Prostate Cancer InfoLink is not entirely surprised by this outcome. It is apparent that ipilimumab does have some activity in the treatment of at least some men with progressive forms of prostate cancer. However, it was hoping a lot to think that the demonstrated activity would translate in a real overall survival benefit in a subset of patients with very advanced forms of metastatic disease. The level of adverse effects of Grade 3 and higher is also an issue that may be particularly problematic in men who have very advanced forms of prostate cancer.

The real question is going to be whether ipilimumab has a role either earlier in the disease or in a definable subset of patients that can be identified through the use of a specific marker for CTLA-4 activity (or similar). To that point, a senior Bristol-Myers Squibb executive is quoted as follows in the media release:

While we are disappointed that the primary endpoint of overall survival was not met, we remain encouraged that results in this advanced population support the potential role of immunotherapies for prostate cancer. We are committed to continuing our development of Yervoy in prostate cancer.

This is not going to be the end of the ipilimumab story in management of prostate cancer, but it is clear that the potential value of this drug for most men with mCRPC who have failed chemotherapy is low in the extreme.

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