No improvement in survival or in any key secondary end point was observed when the checkpoint inhibitor atezolizumab (Tecentriq) was added to enzalutamide (Xtandi) for the treatment of metastatic castration-resistant prostate cancer (CRPC) in the phase 3 IMbassador250 trial. The study results were presented at the 2020 American Association for Cancer Research virtual annual meeting.
Fueled by success in treatments for other genitourinary malignancies (eg, kidney and bladder cancer), investigators have hoped that immune checkpoint inhibitor therapy would show benefits in prostate cancer.
“This is the first phase 3 trial to study a checkpoint inhibitor combination in metastatic CRPC. There was no evidence of differences in cancer control between the 2 arms and no improvement in overall survival,” said lead investigator Christopher J. Sweeney, MBBS, Institute Physician, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA.
The phase 3 IMbassador250 clinical trial included 759 patients (median age, 70 years) with metastatic CRPC whose disease progressed after receiving abiraterone and were ineligible or refused to take a taxane regimen. Patients were randomized in a 1:1 ratio to atezolizumab 1200 mg intravenously every 3 weeks plus enzalutamide 160 mg daily or to the same dose of atezolizumab without enzalutamide. Treatment was continued until the loss of clinical benefit or until unacceptable toxicity. Stratification included the previous use of a taxane, the presence of liver metastasis, normal lactate dehydrogenase versus upper limit of normal, and pain severity within the past 24 hours.
At baseline, 55% of the patients had received previous taxane-containing regimens; 33% had visceral disease (11% liver metastases), 90% had bone metastasis, and 30% had lymph node metastasis. PD-L1 testing revealed that only approximately 3% of tumors had >5% of cells staining positive.
After 23 months of treatment, the study was stopped for futility by an independent monitoring committee. In addition to the lack of a survival benefit with the addition of atezolizumab, no survival benefit was observed for the immune checkpoint inhibitor in any prespecified subgroup.
Atezolizumab plus enzalutamide did not improve the key secondary end points compared with enzalutamide alone, including response rates, stable disease, progressive disease, duration of response, and prostate-specific antigen response. The 12-month overall survival rates were 64.7% with the combination and 60.6% with enzalutamide monotherapy. The median duration of treatment exposure was 3.5 months and 4.5 months, respectively, in the atezolizumab plus enzalutamide arm versus 4.2 months with enzalutamide monotherapy.
Treatment-related adverse events were more frequent with the combination therapy. Grades 3 and 4 events occurred in 28% of the combination arm versus 10% in the monotherapy arm. The rate of adverse events leading to treatment discontinuation was 14% versus 6%, respectively. In all, 7 treatment-related deaths occurred in the combination arm versus 1 death in the monotherapy arm.
Adverse events of special interest, including rashes, hypothyroidism, hepatitis, pneumonitis, colitis, and myasthenia, were more frequent in the atezolizumab plus enzalutamide arm compared with enzalutamide alone.
CRPC: A “Cold” Tumor
According to the invited discussant Padmanee Sharma, MD, PhD, T.C. and Jeanette Hsu Endowed Chair in Cell Biology, Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, disappointing results in monotherapy trials of checkpoint inhibitors in metastatic CRPC suggest that combination therapies are needed to improve response rates, but combination trials have not panned out so far.
“The idea of adding a checkpoint inhibitor is to shift prostate cancer from being an immunologically ‘cold’ tumor with few T-cells to become more of a ‘hot’ tumor,” she explained.
“There are few mutations in prostate cancer, and as a result, the effector T-cells may not be able to recognize an adequate number of antigens to mount a tumor response. The impact of enzalutamide on the microenvironment is unknown. Poor responses have been observed in prostate cancer after multiple prior therapies. There are multiple immunosuppressive pathways within the prostate tumor microenvironment, and PD-1/PD-L1–targeting agents may not sufficiently target all these immunosuppressive pathways,” Dr Sharma commented.