PracticeUpdate Oncology February 2019

EDITOR’S PICKS 7

Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade JAMA Oncology Take-home message • In this case series of 1346 patients with prostate cancer who underwent paired tumor and germline sequencing, 32 of 1033 (3.1%) had micro- satellite instability-high or mismatch repair-deficient disease, of whom 7 (21.9%) carried a germline mutation in a Lynch syndrome-associated gene. Of 11 patients who received an anti–PD-1/PD-L1 agent, 5 had durable clinical benefit. • The microsatellite instability-high/mismatch repair-deficient phenotype is uncommon but clinically important in prostate cancer and can be somatically acquired during disease evolution. Jeffrey Wiisanen MD Abstract IMPORTANCE The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prev- alence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. OBJECTIVE To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. DESIGN, SETTING, AND PARTICIPANTS In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. MAIN OUTCOMES AND MEASURES Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immu- nohistochemistry for MMR protein expression were performed in select cases. RESULTS Among the 1033 patients who had adequate tumor quality for MSIsensor anal- ysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/ dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-as- sociated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/ dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. CONCLUSIONS AND RELEVANCE The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/ dMMR phenotype respond, further studies should explore mechanisms of resistance. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol 2018 Dec 27;[EPub Ahead of Print], W Abida, ML Cheng, J Armenia, et al. www.practiceupdate.com/c/77948

Abstract BACKGROUND Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmuno- therapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the proto- col-specified efficacy threshold had been met. RESULTS A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with ben- damustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease pro- gression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibru- tinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall sur- vival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibruti- nib-containing regimens (74% with each regimen). CONCLUSIONS Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progres- sion-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. Ibrutinib Regimens Versus Chemoimmunotherapy in Older Patients With Untreated CLL. N Engl J Med 2018 Dec 01;[EPub Ahead of Print], JA Woyach, AS Ruppert, NA Heerema, et al. www.practiceupdate.com/c/77047

VOL. 3 • NO. 1 • 2019