Genitourinary Cancers Symposium
Genitourinary Cancers Symposium
February 15, 2019
4 min read

Nivolumab plus ipilimumab shows activity in metastatic castration-resistant prostate cancer

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Padmanee Sharma, MD
Padmanee Sharma

SAN FRANCISCO — Nivolumab plus ipilimumab demonstrated activity in pretreated men with metastatic castration-resistant prostate cancer, according to initial findings from the phase 2 CheckMate 650 study presented at Genitourinary Cancers Symposium.

In addition, the safety profile for the combination appeared consistent with the dosing schedule.

“This was the first combination trial of two immune checkpoint therapies in prostate cancer,” Padmanee Sharma, MD, professor in the department of genitourinary medical oncology, division of cancer medicine at The University of Texas MD Anderson Cancer Center, said in a press release. “These results support the idea that immune checkpoint blockade can play an important role in the treatment of these patients and provide the foundation to test this strategy in a larger clinical trial.”

Men with prostate cancer have demonstrated insufficient benefit from immune checkpoint inhibitor monotherapy, which researchers speculate is because of the immunologically “cold” tumor microenvironment.

Anti-CTLA-4 treatment with single-agent ipilimumab (Yervoy, Bristol-Myers Squibb) has yielded modest clinical activity based on PSA response rate and PFS. Moreover, although ipilimumab prompts T-cell infiltration in men with prostate cancer, subsequent induction of compensatory immune inhibitory pathways may hinder T-cell responses.

“These data suggest that augmented immune cell infiltration alone is insufficient for optimal antitumor activity and provide a rationale for combining immune checkpoint inhibitors to potentially boost antitumor responses,” Sharma said during her presentation.

In the current study, Sharma and colleagues evaluated the safety and efficacy of nivolumab (Opdivo, Bristol-Myers Squibb), which targets PD-1, plus ipilimumab in two cohorts of men with metastatic castration-resistant prostate cancer. Men received 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for four doses, followed by 480 mg nivolumab monotherapy every 4 weeks.

The first cohort included asymptomatic or minimally symptomatic men who had progressed after treatment with second-generation hormone therapy and had not received chemotherapy (n = 45; median age, 69 years; range, 48-85). The second cohort consisted of men who progressed after taxane-based chemotherapy (n = 45; median age, 65 years; range, 46-84).

Objective response rate and radiographic PFS based on Prostate Cancer Working Group 2 criteria served as the study’s coprimary endpoints. Safety served as a secondary endpoint.

Seventy-eight men had a follow-up of at least 6 months. Median follow-up was 11.9 months for the first cohort and 13.5 months for the second cohort.

ORR among men with baseline measurable disease was 25% (95% CI, 11.5-43.4) in the first cohort and 10% (95% CI, 2.1-26.5) in the second cohort.


Median time to response was 1.9 months in the first cohort and 2.1 months in the second cohort.

Six patients (17.6%; 95% CI, 6.8-34.5) in the first cohort and four (10%; 95% CI, 2.8-23.7) in the second cohort achieved PSA response, defined as a PSA decline of at least 50% from baseline.

Five patients in the first cohort and two patients in the second cohort demonstrated a PSA of less than 0.2 ng/mL. Of these patients, four from the first cohort and one from the second cohort also had ongoing objective responses, Sharma said.

The researchers also conducted exploratory biomarker analyses of the associations of PD-L1, homologous recombination deficiency, DNA damage repair and tumor mutational burden.
vs. less than 1% (cohort 1, 33.3% vs. 19%; cohort 2, 40% vs. 0%), DNA damage repair positivity vs. negativity (cohort 1, 33.3% vs. 29.4%; cohort 2, 40% vs. 11.1%), homologous recombination deficiency positivity vs. negativity (cohort 1, 50% vs. 26.3%; cohort 2, 50% vs. 16.7%), or high vs. low tumor mutational burden (cohort 1, 50% vs. 9.1%; cohort 2, 50% vs. 0%).

Although tumor mutational burden is comparatively low in prostate cancer compared with other cancer types, researchers observed a significant association between higher tumor mutational burden and better outcomes in men with metastatic castration-resistant prostate cancer.

Researchers also observed higher likelihood of PSA response (50% vs. 9.1%) and achieving PSA less than 0.2 ng/mL (50% vs. 4.5%) among men with PD-L1 expression of 1% or higher vs. less than 1% in cohort 1, but not cohort 2. High vs. low tumor mutational burden was associated with PSA response (38.5% vs. 0%) and achieving PSA less than 0.2 ng/mL (30.8% vs. 0%) also in cohort 1, but not cohort 2.

Researchers did not observe associations between DNA damage repair or homologous recombination deficiency for PSA response.

Radiographic PFS was 5.5 months (95% CI, 3.5-7.1) in cohort 1 and 3.8 months (95% CI, 2.1-5.1) in cohort 2. When researchers evaluated radiographic PFS by PD-L1 status in cohort 1, they observed a median radiographic PFS of 5.6 months (95% CI, 1.9-not estimable) among men with PD-L1 expression of at least 1% and 3.9 months (95% CI, 2.7-5.5) among men with PD-L1 expression of less than 1%.

Patients in cohort 1 with DNA damage repair-positive or homologous recombination deficiency-positive tumors also demonstrated longer median radiographic PFS, but the difference was not significant. High tumor mutational burden was associated with significantly longer radiographic PFS (7.4 months vs. 2.4 months; P < .0001).


Median OS was 19 months (95% CI, 11.5-not estimable) in cohort 1 and 15.2 months (95% CI, 8.4-not estimable) in cohort 2.

Overall, 42.2% of men in the first cohort experienced grade 3 to grade 5 treatment-related adverse events, as did 53.3% of men in the second cohort.

Treatment-related adverse events led to discontinuation in 33.3% of the first cohort and 35.6% of the second cohort.

The most common adverse events were diarrhea, fatigue, skin rash, nausea and hypothyroidism. Four patients, two in each cohort, died of treatment-related adverse events.

“In malignancies where immune checkpoint monotherapy has shown limited activity, nivolumab plus ipilimumab demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer,” Sharma said. “Deep and durable objective responses, as well as PSA less than 0.2 ng/mL, were observed in a subgroup of patients. Preliminary data suggest that biomarkers may have a role in identifying patients with metastatic castration-resistant prostate cancer likely to respond to immunotherapy.” – by Jennifer Byrne


Sharma P, et al. Abstract 239669. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Disclosures: Sharma reports stock and other ownership interests in Constellation Pharmaceuticals, Evelo Therapeutics, Jounce Therapeutics, Kite Pharma, Neon Therapeutics and Oncolytics; and consultant/advisory roles with Amgen, Astellas Pharma, AstraZeneca, BigAtla, Bristol-Myers Squibb, Constellation Pharmaceuticals, EMD Serono, Evelo Therapeutics, GlaxoSmithKline, Jounce Therapeutics, Kite Pharma, Merck Sharpe & Dohme, Neon Therapeutics, Oncolytics and Pieris Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.