Men with AR-V7-positive prostate cancer seem to respond positively to a combination therapy with ipilimumab (Yervoy) and nivolumab (Opdivo).
Men with AR-V7-positive prostate cancer seem to respond positively to a combination therapy with ipilimumab (Yervoy) and nivolumab (Opdivo) if they have specific mutations, according to a study published in Oncotarget (2018; 9:28561-71).
In 2014, researchers from Johns Hopkins Medicine, Baltimore discovered the androgen-receptor splice variant 7 (AR-V7), a prostate cancer type that’s generally resistant to newer hormonal therapies and responds poorly to taxane chemotherapies. AR-V7 often kills men with the diagnosis in 6 to 9 months.
In a phase II trial of 15 patients with AR-V7 expressing circulating tumor cells, Johns Hopkins researchers led by Emmanuel S. Antonarakis, MD, gave each patient nivolumab, 3 mg/kg plus ipilimumab, 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab, 3 mg/kg every 2 weeks.
Six of the men had DNA Repair Deficiency, or DRD, mutations, including BRCA2, ATM, and ERCC4.
The authors found that ipilimumab plus nivolumab treatment was efficacious in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population. Two of the 15 men had a decrease in PSA of at least 50%. One-quarter of patients with measurable tumors achieved an objective response, in which tumors shrank partially or completely with combination immunotherapy. At least two of the patients remained alive for more than 18 months.
The combination therapy did not seem to pose additional treatment-related safety concerns compared to prior studies testing this combination in other tumor types, according to the authors.
Next -Dr. Pardoll: Study offers new insight in 3 areasDrew M. Pardoll, MD, PhD, of Johns Hopkins Medicine told Urology Times the study offers new insight in three areas: It’s the first to demonstrate a signal of activity of immunotherapy in prostate cancer, which has previously been considered refractory to immunotherapy; it’s the first to demonstrate the combination of anti-CTLA-4 and anti-PD-1, which has been successful in other cancer types such as kidney, lung, and melanoma, can have activity in some patients with prostate cancer; and it defines a new potential genetic subset of prostate cancer, Double strand DNA Repair deficient (DDRd), that responds to immunotherapy.
“Previously, anti-PD-1 was shown to have activity in… about 2% of prostate cancers that were marked by a different genetic marker called MisMatch Repair deficiency (MMRd). The DDRd subset of prostate cancer is roughly 10 times as common-about 20% of prostate cancer. DDRd is a higher proportion of the AR-V7+ prostate cancer group-about 40%-so the signal of efficacy in the AR-V7+ group may reflect efficacy in DDRd prostate cancers in general,” said Dr. Pardoll, who is not an author of the study.
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Providers might consider testing for AR-V7 and/or DDRd to help define which patients should receive this combination immunotherapy in the future. But it’s early to make practice-based recommendations at this time, according to Dr. Pardoll.
This was a small study, not powered to detect clinical effects in the overall patient group that meet statistical significance, he said.
“The point of these types of small studies, beyond assessing tolerability/toxicity of the regimen, is to identify ‘signals’ of activity and possibly subsets of patients with a greater signal of activity. That was achieved [with] an interesting number of responses in the DDRd group of AR-V7+ prostate cancers,” Dr. Pardoll said. “That signal in a small number of patients does not prove the efficacy of this immunotherapy combination in this subset of patients, but rather defines a new group that warrants follow-up with a larger study, which is being undertaken.”
This expanded study is currently seeking new patients. To learn more, click here.
Bristol-Myers Squibb sponsored the study and provided the drugs. Dr. Antonarakis is a consultant/adviser to Janssen, Astellas, Dendreon, Medivation, ESSA, AstraZeneca, Clovis, and Merck, and has received institutional funding from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck . He co-invented a biomarker technology that has been licensed to Qiagen. Several of his co-authors have one or more disclosures related to pharmaceutical companies.
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