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Ipilimumab prolongs overall survival in metastatic castration-resistant prostate cancer

European Urology
Reuters Health - 08/09/2020 - Treatment with ipilimumab following radiotherapy to bone metastases in men with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel is associated with improved overall survival, according to final results from the CA184-043 trial.

"This should prompt us to start revisiting immunotherapy in mCRPC," Dr. Karim Fizazi of Institut Gustav Roussy, University of Paris Saclay, in Villejuif, told Reuters Health by email. "Using immunotherapy was almost stopped 5 years ago after two phase-3 trials had failed to demonstrate overall survival improvement. These data indicate that some men clearly benefit and also that early assessments of survival may not be appropriate to assess immunotherapy benefits."

The monoclonal antibody ipilimumab blocks the inhibitory signal mediated by CTLA-4, thereby enhancing antitumor immunity at the expense of immune-related side effects. In earlier trials, including 043, ipilimumab significantly improved progression-free survival but not overall survival.

In the current study, Dr. Fizazi and colleagues evaluated mature results of the 043 trial with an additional two years of follow-up beyond the primary analysis.

The analysis included all 799 participants in the study, including 399 men in the ipilimumab arm and 400 men in the placebo arm.

Overall, 49 men in the ipilimumab group and 29 men in the placebo group remained alive, with a median follow-up of 50 months for the survivors, the researchers report in European Urology.

Overall survival curves crossed between seven and eight months, after which survival in the ipilimumab arm remained superior to that in the placebo arm. Median overall survival was 11.0 months with ipilimumab, compared with 10.0 months with placebo.

Overall survival rates were significantly higher in the ipilimumab arm than in the placebo arm at two years (25% vs. 17%), three years (15% vs. 7.9%), four years (10% vs. 3.3%) and five years (7.9% vs. 2.7%).

The safety profile for ipilimumab was similar to that reported previously, with immune-related adverse events affecting mostly the gastrointestinal tract and skin and, to a lesser extent, the liver and endocrine organs. Most of these events occurred during the initial four doses of ipilimumab.

"It's becoming key to identify biomarkers predicting immunotherapy benefits," Dr. Fizazi said. "This long-term analysis clearly suggests that only about 10% of men with mCRPC derive major long-term benefits from CTLA-4 targeted immunotherapy."

"Given the side effects of this treatment, it makes no sense treating 10 patients to get only one potentially benefiting," he said. "Fortunately, potential biomarkers (MSI status, cdk12 loss, perhaps tumor mutation burden, etc.) seem to be emerging."

"This should prompt the pharma industry and academia to stop conducting randomized trials in all-comer mCRPC men and rather to preselect subgroups based on biomarkers, to show more meaningful improvements," Dr. Fizazi concluded.

Dr. Russell Pachynski of Washington University, in St. Louis, Missouri, who specializes in prostate cancer, told Reuters Health by email, "Since there's no (US or EU) approval for checkpoint-inhibitor immunotherapy in prostate cancer, (the new finding) doesn't practically change what most providers will or should do."

"But," he added, "there are retrospective data from the only approved immunotherapy for prostate cancer, sipuleucel-T, suggesting that using immunotherapy earlier (i.e., at lower PSA) results in larger improvements in survival from the drug. So, the data looking at the 'good prognosis' patients is supportive of that general concept, that is, using immunotherapy earlier."

"After many trials looking at checkpoint immunotherapy in metastatic prostate cancer didn't show much benefit, a lot of focus was placed on tumor types that were generally more responsive to these drugs," he explained. "This report shows that there is some - albeit small - long-term survival benefit to single-agent immunotherapy in these patients."

"The trick will be improving this using combinations of drugs, and this is going on in a number of trials," Dr. Pachynski said. "So, lots of work to do in prostate-cancer immunotherapy, but we're starting to see some benefit!"

He added, "We need to be smarter about how to optimize immunotherapy in prostate cancer, now that we've seen some but small benefit of single agent checkpoint inhibitors in metastatic prostate cancer. Perhaps focusing less on T cell-based therapies and more on those targeting the myeloid or innate components and thinking more about how to favorably alter the bone tumor microenvironment, which comprises the majority of metastatic sites in these patients."

Dr. Guru P. Sonpavde of Dana Farber Cancer Institute, Harvard Medical School, in Boston, who also studies prostate cancer, told Reuters Health by email, "These data suggest that a subset of patients with mCRPC may enjoy delayed benefit from ipilimumab. However, this final analysis is not practice-changing, given the negative initial analysis."

"The data are clearly intriguing, and further rational development of ipilimumab and other immunotherapeutics in rationally selected mCRPC patients guided by accumulating data for precision medicine may be warranted," he said.

"The development of a role for immunotherapeutics (and other agents) should proceed concurrently with developing predictive biomarkers of benefit," added Dr. Sonpavde, who was not involved in the study.

Bristol-Myers Squibb funded the trial, employed two of the authors and had various relationships with several others, including Dr. Fizazi, and with Dr. Sonpavde.

By Will Boggs MD

SOURCE: https://bit.ly/34OiVXP European Urology, online August 15, 2020.

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