Combining nivolumab and ipilimumab may be an effective treatment strategy for metastatic castration-resistant prostate cancer. In a phase II trial, 25% of patients who received the combination following hormone therapy had an objective response. However, the combination was associated with considerable side effects that caused many patients to discontinue treatment.

Combining the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) with the CTLA4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) may be a promising treatment strategy for metastatic castration-resistant prostate cancer, according to results presented in February at the 2019 Genitourinary Cancers Symposium in San Francisco, CA. In the phase II CheckMate 650 trial, the combination elicited encouraging objective response rates (ORR) but was associated with considerable side effects.

Immune checkpoint inhibitors have been successful in treating cancers with a high tumor mutational burden (TMB), such as melanoma and lung cancer, yet they have not worked well in patients with immunologically “cold,” low-TMB tumors, such as prostate cancer, explains Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who presented the results.

However, in a preclinical study, ipilimumab increased PD-1 and PD-L1 levels, leading researchers to hypothesize that it could drive T cells into prostate tumors, and that nivolumab could subsequently block compensatory immune pathways on T cells such as PD-1 (Nat Med 2017;23:551–5). Consequently, “we proposed the idea of combination therapy,” Sharma says.

In the new trial, Sharma and her team divided 90 patients with metastatic, castration-resistant prostate cancer into two cohorts: Cohort 1 had previously received second-generation hormone therapy, and cohort 2 had received hormone therapy and chemotherapy. Of 32 evaluable patients in cohort 1, 25% had an objective response, as did 10% of 30 evaluable patients in cohort 2. Patients in both cohorts whose tumors had a PD-L1 level of at least 1%, homologous repair deficiency mutations, DNA damage repair mutations, or a TMB greater than the median of 74.5 mutations had enhanced responses.

Almost all patients experienced side effects. Grade 3 to 5 adverse events—most commonly diarrhea and colitis—occurred in 42.2% of cohort 1 and 53.3% of cohort 2, leading to four deaths. Consequently, 51.1% and 44.4% of cohorts 1 and 2, respectively, discontinued treatment.

“For the first time, we are getting reproducible clinical responses that appear to be durable,” Sharma says. “The main takeaway is that we can certainly overcome this idea that cold tumors don't respond to immune checkpoint therapy.”

Emmanuel Antonarakis, MD, of Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, MD, who was not involved in the trial, notes that “the toxicities are not trivial, and remain a significant concern.” Future trials, he adds, should focus on patients with specific biomarkers. “The efficacy appears to be restricted to certain biomarker subsets,” he says. “You don't want to expose patients to a futile therapy that could be highly toxic if the preliminary data suggest that they will probably not respond.”

Sharma's team is expanding CheckMate 650 to gain insight into the predictive value of biomarkers. They also plan to adjust drug dosing and frequency to reduce side effects.

“In my opinion, there's an unmet need to develop nonhormonal and nonchemotherapy approaches for advanced prostate cancer, and one of the most obvious would be immunotherapy,” Antonarakis says. “There is clearly a subset of patients that respond very profoundly and in a durable fashion with these drugs. I just think we need to do a better job of identifying who they are.” –Catherine Caruso

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©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.