Many of the patients experienced fairly significant toxicities on treatment, and treatment-related adverse events led to discontinuation of treatment in 33.3% of patients in cohort 1 and 35.6% of patients in cohort 2.

“The toxicity profiles of these agents are very concerning; some adjustments in the doses or perhaps a different combination is needed to move this forward,” said Dr Dorff.

In addition to the graded toxicities, almost two-thirds of patients required steroids to manage immune-related adverse events, and 4 deaths were observed out of the 90 patients.

“The number of deaths is also concerning, as it is higher than what you even might see with a chemotherapy-based trial. Maybe there is potential for some durable responses in some people, but this has to be studied against the risk they may face,” said Dr Dorff.


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However, several trials of immunotherapies in other tumor types have also reported similarly high toxicities, and there is hope that doses and dosing schedules can be tweaked so that these drugs can be a viable treatment option for some patients with advanced cancers.

“Although high, the incidence of tumor-related adverse events and the proportion of patients who needed high-dose corticosteroids are comparable to studies in other tumors. For example, in the renal cell carcinoma CheckMate trial, about 40% of patients needed high-dose steroids and the grade 3 to 4 toxicities are comparable,” noted Dr Wei.

“We have to address this toxicity issue and we will be looking at this in the expansion of the trial. If we can minimize them, we can keep patients on treatment longer and we can also improve efficacy,” said Dr Sharma.

So, what does the recent study mean for immunotherapy treatment of patients with mCRPC in the present day?

“I don’t think patients with prostate cancer should receive this combination outside of a clinical trial. This isn’t something that will impact clinical practice immediately; it is valuable, though. The analysis of factors like TMB may emerge with other biomarkers to enable us to select patients that will respond,” said Dr Dorff.

“This research is a work in progress. I don’t think it will change my clinical practice today, but it is an informative study, which will influence the next generation of trials,” said Dr Wei.

The next step for the work is an expanded phase 2 trial involving more than 400 patients with prior treatment with docetaxel, randomized across 4 treatment arms. One of the main goals is to reduce the toxicity of the treatments.

“This study will provide insights into several important clinical questions — for example, is 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab safer, and do you use significant clinical activity by using a lower dose of ipilimumab? It will also allow more vigorous investigation of potential biomarkers on top of TMB — PD-L1 levels, for example,” said Dr Wei.

Two arms will involve nivolumab and ipilimumab at different doses and schedules and the other 2 will involve ipilimumab plus cabazitaxel. There is hope that the study will provide more evidence that anti–CTLA-4 agents could play a more significant role in ICI treatment approaches.

“Although anti–PD-1 and PD-L1 have been the backbone in most ICI treatment approaches, scientifically it could make sense to use a anti–CTLA-4 drug to drive cold tumors to hot. Most people use anti–PD-1, but these 2 drugs work so differently, and we know anti–CTLA-4 increases tumor-infiltrating lymphocytes in immunologically cold prostate cancers,” said Dr Sharma.

References

  1. Sharma P, Pachynski RK, Narayan V, et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. 2020;S1535-6108(20):30418-30419. doi:10.1016/j.ccell.2020.08.007
  2. Forster V. Ipilimumab May Help Some Patients With Prostate Cancer — Even Those With Low TMB. Cancer Therapy Advisor. Published May 6, 2020. Accessed October 8, 2020.