Dr. Oh notes that in order to advance prostate cancer therapy we need to identify new targets with novel approaches. This includes the PI3K/Akt pathway considering that there is crosstalk between the androgen receptor and PI3K/Akt pathways leading to prostate cancer growth. The key finding in the phase 1b/2 study of enzalutamide with LY3023414 (LY) or placebo in patients with mCRPC after progression on abiraterone was that patients treated with combination therapy had progression-free survival (PFS) advantage compared to enzalutamide alone (HR 0.65, 95%CI 0.43-0.99):
Furthermore, this was confirmed in patients that were AR-V7 negative that received combination therapy, resulting in an improvement in radiographic progression-free survival (rPFS) (HR 0.52, 95% CI 0.28-0.95). Dr. Oh noted that recent trials targeting the PI3K/Akt pathway have been disappointing and thus, that this positive study presented by Dr. Sweeney and colleagues is exciting news.
Dr. Oh notes that this was mostly a tolerable regimen with only moderate GI side effects, however, the benefits appear modest until you select subsets of patients including AR-V7 negative and radiographic progression only. Unfortunately, PTEN loss did not predict a benefit; LY3023414 will not be developed further and we await trials of Akt inhibitors, including the phase III IPATential 150 trial.
KEYNOTE-365 cohort C noted a prostate-specific antigen (PSA) response in 26% of the total population (40% in RECIST measurable disease), the objective response rate was 20%, and disease control rate was 33% among men treated with pembrolizumab and enzalutamide after previous abiraterone therapy. Dr. Oh states that the PSA response rates in cohort C are comparable to cohort A (pembrolizumab plus olaparib) and cohort B (pembrolizumab plus docetaxel plus prednisone). Furthermore, the PSA response rate of 26% also compared to the 31% when enzalutamide is used alone after abiraterone. Dr. Oh wonders if the higher PSA response rate in measurable disease patients is significant – although not tested in this study, this may be due to different genetics, these tumors may be more immunogenic, or have greater PD-L1 positivity. He thinks the overall measurable response rate of 20% is promising, considering that pembrolizumab alone after docetaxel has a response rate of 10%. This combination of pembrolizumab plus enzalutamide will move forward with the phase III KEYNOTE-641.
Patients with copy number loss of 17q22 have enzalutamide resistance and subsequent poor prognosis in the setting of mCRPC. Dr. Oh notes that of 124 genes downregulated in enzalutamide resistance, 8 tumor suppressor genes were identified in this study. Loss of RNF43 and SRSF1 on 17q22 leads to activation of multiple genes that promote prostate cancer growth and a survival disadvantage (19 vs 42 months). Dr. Oh states that molecular diagnostics have identified resistance mechanisms, however, we are still left in the same place we started with limited therapeutic choices. Currently, we cannot replace lost tumor suppressors and we still have trouble blocking some activated kinases.
Presented by: William K. Oh, MD, Icahn School of Medicine at Mount Sinai Tisch Cancer Institute, New York, NY
Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA