Researchers may be able to predict which patients with CRPC are most likely to have poorer outcomes while undergoing targeted therapy, according to the results of the PREMIERE trial.
Gerhardt Attard, MD, PhD
By assessing plasma androgen receptor (AR) gene status assessment with multiplex droplet digital PCR (ddPCR), European researchers could predict which patients with castration-resistant prostate cancer (CRPC) were most likely to have poorer outcomes while undergoing targeted therapy, according to results from the PREMIERE trial published in the Annals of Oncology.
Researchers said there was a “significant association” for AR gain and poorer overall survival (OS) for both chemotherapy-naïve patients (HR, 3.98; 95% CI, 1.75-9.10; P <.001) and patients previously treated with docetaxel (HR, 3.81; 95% CI, 2.28-6.37; P <.001). AR gain was also associated with poorer OS for chemotherapy-naïve patients treated with enzalutamide (Xtandi) or abiraterone acetate (Zytiga; HR, 2.18; 95% CI, 1.08-4.39; P = .03) and for patients previously treated with docetaxel (HR, 1.95; 95% CI, 1.23-3.11; P = .01).
Men with AR gain were more likely to die during the study whether they were undergoing treatment with enzalutamide (HR, 3.98; 95% CI, 1.74-9.10; P <.001) or abiraterone (HR, 3.81; 95% CI, 2.28-6.37; P <.001). Researchers also noted a significant association between AR mutants and poorer OS in post-docetaxel patients treated with abiraterone (HR, 3.26; 95% CI, 1.47—not reached; P = .004).
“Abiraterone and enzalutamide are excellent treatments for advanced prostate cancer and some men can take these drugs for years without seeing a return of their cancer,” coauthor Gerhardt Attard, MD, PhD, team leader in the Centre for Evolution and Cancer at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, said in a statement. “But in other men, these drugs do not work well and the disease rapidly returns. Currently there is no approved test to help doctors choose whether these are the best treatments for an individual.
“We have developed a robust test that can be used in the clinic to pick out which men with advanced prostate cancer are likely to respond to abiraterone and enzalutamide, and which men might need alternative treatments.”
Researchers noted a trend for poorer progression-free survival (PFS) associated with AR mutations (HR, 2.10; 95% CI, 0.98-4.51; P = .057). Treatment with abiraterone versus enzalutamide and chemotherapy status were not significant predictors for outcome according to Cox models.
Researchers recruited 171 men participating in separate studies in London and Meldola, Italy, for the primary cohort. These patients initiated enzalutamide or abiraterone from January 2011 to June 2016. Eight post-docetaxel patients were AR point mutation positive before beginning treatment with abiraterone. All 8 patients had received prior chemotherapy.
The second, confirmatory cohort made up the PREMIERE trial, which was sponsored and conducted by the Spanish Genito-Urinary Oncology Group (SOGUG). Ninety-eight patients were treated at 16 sights from February 2015 and November 2015.
To determine plasma AR status, researchers used an optimized multiplex AR copy number ddPCR assay on 2 ng to 4 ng DNA from all pretreatment samples, plus an additional 42 samples collected after disease progression.
Prior to initiation with enzalutamide, researchers collected plasma from 94 patients in the PREMIERE trial who had progression.
Eleven patients (12%) in this cohort had AR gain. Seven patients (20%) with AR gain also had had circulating tumor cells (CTCs). Overall, CTCs were detected in 35 patients (37%).
As in the primary cohort, men with plasma AR gain had shorter OS (HR, 11.08; 95% CI, 2.16-56.95; P = .004). Researchers said men with AR gain also had shorter PSA-PFS (HR, 4.33; 95% CI, 1.94-9.68; P <.001) and radiographic PFS (HR, 8.06; 95% CI, 3.26-19.93; P <.001).
“Developing tests that help doctors predict how likely a treatment is to work will prevent patients from suffering unnecessary side effects from treatments that are unlikely to benefit them,” Emma Smith, PhD, science information manager at Cancer Research UK, said in a statement. “If further studies confirm this test is reliable, it could also help doctors choose better options for men whose prostate cancer is unlikely to respond to standard treatments.”
Conteduca V, Wetterskog D, Sharabiani MTA, et al. Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study [published online May 3, 2017]. Ann Oncol. doi: 10.1093/annonc/mdx155.