Progress in Understanding What Is Being Statin(ed) in Prostate Cancer

tation status) on objective response rates with nivolumab, although this difference was not observed in the overall data analysis reported by Larkin et al.1 Furthermore, while there are data to suggest synergy between BRAF-directed therapy and PD-1 blockade (an area of active investigation, although not approved for clinical use), current data do not support clear differences in clinical response rates to PD-1 blockade that can be related to the drug mechanism of action of prior BRAF inhibitor therapy. However, factorsassociatedwithpriorBRAF inhibition,suchasanincreased baseline tumor size after prior therapy, may have an impact on response rates to PD-1 blockade, as previously described.2 Overall, the results do suggest a similar response rate to PD-1 blockade in patients with and without BRAF mutant melanoma in this retrospective data analysis including a heterogeneous study population. The results are also consistent with those of priorstudiesofimmunetherapywithipilimumab3 inwhichBRAF mutation status does not have an impact on objective response rates and are also consistent with a prior report of PD-1 blockade with pembrolizumab in which response rates were similar in the BRAF-mutant and nonmutant patients enrolled in a large clinical trial.4 A prospective randomized clinical study in a uniform study population would be required to confirm that response rates are truly equal in patients with or without BRAF-mutant melanoma, and in patients with and without prior BRAF inhibitor therapy among the BRAF-mutant patients. The results are applicable to patients similar to those eligible for the clinical trials included in the analysis; that is, patients with a good performance status and normal organ function can be considered for treatment with PD-1 blockade with nivolumab regardless of BRAF mutation status. However, clinicians should exercise caution in applying these results to patients who would not meet the trial eligibility criteria of the study population—for example, patients with a poor performance status, because response rates to nivolumab may not be similar in patients with and without BRAF mutations in a nontrial population. BRAF-directed therapy may offer a higher chance of response and clinical benefit in some patients with BRAF-mutant melanoma and should be considered in all patients with BRAF-mutant melanoma. It is clear that patients both with and without BRAFactivating mutations gain benefit from PD-1 blockade, with durable responses observed in both subsets of patients, regardless of prior therapies. Ongoing studies will further define the role of sequencing of BRAF-targeted therapy and PD-1 or CTLA-4 blockade on clinical outcomes. Clinical trials that include PD-1 blockade as well as novel immune therapy combination studies or targeted therapy combination studies can be considered among the first line of therapy options for all patients with advanced melanoma.