The addition of the checkpoint inhibitor atezolizumab to enzalutamide failed to improve overall survival compared with enzalutamide alone in men with metastatic castration-resistant prostate cancer in the phase III IMbassador250 trial, according to results presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting.1
“This is the first phase III trial to study a checkpoint inhibitor combination in metastatic castration-resistant prostate cancer. There was no evidence of differences in cancer control between the two arms and no improvement in overall survival,” said lead author Christopher J. Sweeney, MBBS, of Dana-Farber Cancer Institute, Boston.
There was no evidence of differences in cancer control between the two arms and no improvement in overall survival.— Christopher J. Sweeney, MBBS
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In the study, programmed cell death ligand 1 (PD-L1) expression did not identify a population that benefited from the addition of atezolizumab to standard therapy. After 23 months of treatment, an independent monitoring committee stopped the study for futility when it was evident there was no chance to show improvement in overall survival for the experimental arm. However, Dr. Sweeney noted, ongoing biomarker studies may provide some insights as to which patients might benefit.
“Despite the availability of currently life-extending therapies for metastatic castration-resistant prostate cancer, the majority of men will die of their disease,” explained Dr. Sweeney. Enzalutamide is an oral androgen receptor inhibitor commonly used to treat metastatic castration-resistant prostate cancer, and atezolizumab is an anti–PD-L1 immune checkpoint inhibitor with activity in “a vast array of cancers,” he added. Checkpoint inhibitors have been a game-changer in many solid tumors, and investigators are hoping they can improve outcomes for patients with prostate cancer.
“Immunotherapy has already been used to treat castration-resistant prostate cancer. Sipuleucel-T was established as an immunotherapy in 2010, and we wanted to explore whether checkpoint inhibition could have a role in this setting,” Dr. Sweeney noted.
IMbassador250 is a randomized phase III trial that included 759 patients with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone and were ineligible for or refused a taxane regimen. Patients were randomly assigned 1:1 to receive either atezolizumab at 1,200 mg intravenously every 3 weeks plus enzalutamide at 160 mg/d vs the same dose of enzalutamide. Treatment was continued until loss of clinical benefit or unacceptable toxicity. Stratification included a prior taxane, presence of liver metastasis, normal vs upper limit of normal for lactate dehydrogenase (LDH) levels, and pain severity within the past 24 hours.
At baseline, the median age of patients was 70 years; 55% had prior taxane-containing regimens; one-third had visceral disease (11% of them had liver metastases), 90% had bone metastasis, and 30% had lymph node metastasis. PD-L1 testing revealed that about 3% of tumors had more than 5% of cells staining positive.
Not only was there no difference in overall survival between the two treatment arms (15.2 months with atezolizumab vs 16.6 months with enzalutamide-alone), there also was no survival benefit for the checkpoint inhibitor in any prespecified subgroup. Key secondary endpoints failed to show a benefit for atezolizumab plus enzalutamide vs enzalutamide alone, including response rates, stable disease, progressive disease, duration of response, and prostate-specific antigen (PSA) response.
The 12-month overall survival rates were 64.7% with the combination therapy and 60.6% with enzalutamide monotherapy. The median duration of treatment exposure was 3.5 months and 4.5 months, respectively, with atezolizumab/enzalutamide and with enzalutamide monotherapy.
Radiographic progression-free survival was 4.2 months with atezolizumab/enzalutamide vs 4.1 months with enzalutamide. Time to PSA disease progression was 2.8 months in each arm.
Treatment-related adverse events were more frequently reported with the combination therapy. Grade 3 and 4 adverse events occurred in 28% of the combination arm vs 10% in the monotherapy arm.
The rate of adverse events leading to treatment discontinuation was 14% for the combination arm vs 6% for the monotherapy arm. Deaths due to treatment-related causes were reported in seven patients and one patient, respectively.
Regarding adverse events of special interest, more rashes, hypothyroidism, hepatitis, pneumonitis, colitis, and myasthenia occurred in the atezolizumab/enzalutamide arm. “Most of these adverse events occurred in less than 1% of patients, but the cumulative rate of grade 3 and 4 special interest adverse events was 11.5%,” Dr. Sweeney said.
DISCLOSURE: The study was funded by F. Hoffmann–LaRoche, Ltd. Dr. Sweeney holds stock or other ownership interests in Leuchemix; has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Bayer, Celgene, Genentech/Roche, Janssen Biotech, Lilly, Pfizer, and Sanofi; has received institutional research funding from Astellas Pharma, Bayer, Dendreon, Janssen Biotech, Pfizer, and Sanofi; holds patents or intellectual property related to Leuchemix and Exelixis.
1. Sweeney CJ, Gillessen S, Rathkopf D, et al: IMbassador250: A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer. 2020 AACR Virtual Annual Meeting. Abstract CT014. Presented April 27. 2020.
Padmanee Sharma, MD, PhD
Discussant of the IMbassador250 trial, Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, said: “These data indicate that neither anti–PD-1/PD-L1 monotherapy or the combination of anti–PD-1/PD-L1 with enzalutamide is likely to...