Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer.
Chinni SR, Vaishampayan UN, Heilbrun LK, Semaan L, Smith D, Modi D, Monk P, Tejwani S, Sonpavde G, Dobson K, Dickow B, Heath E, Fontana J, and Cher ML. Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer. Cancer Res 2018; 78(13)
Background: TMPRSS2-ERG fusions are highly prevalent in prostate cancer patients, where androgen responsive TMPRSS2 gene promoter fused with coding sequence of ERG transcription factor resulting in androgen mediated expression of ERG factor. Metastatic cancer patients harbor the TMPRSS2-ERG fusions and presence of fusions associate with poor overall survival. The association between ERG transcription factor and anti-androgen therapy (enzalutamide (arm A) vs. bicalutamide (arm B)) responsiveness was evaluated in a randomized trial in metastatic hormone sensitive prostate cancer (mHSPC).
Methods: 40 of 71 patients had evaluable tissue from metastatic biopsy. 18 patients were on enzalutamide arm (A) and 22 patients were on bicalutamide arm (B). PSA was monitored monthly for first 7 months and then every 3 months. Total RNA was isolated from biopsy specimens, QPCR analysis was performed for ERG gene. A standard curve was developed with ERG expressing plasmid in QPCR experiment and the copy number of ERG was determined in the metastatic biopsies. Seven month PSA Response (SMPR) rates were calculated for the high and low subset categories of median-dichotomized ERG copy number. The odds of SMPR was modeled as a function of continuous ungrouped correlative via univariable logistic regression.
Results: 15/40 patients had both pre and post treatment biopsies available. The mean ERG copy number was increased in post treatment biopsy in both arms (enzalutamide, n=10 and bicalutamide, n=5). The mean copy increased (pre= 8541 and post =9789) upon enzalutamide treatment and also increased (pre=17186 and post = 23368) upon bicalutamide treatment. SMPR rates show that low copy number patients responded better (19/20) compared to high copy number patients (14/20). In arm A response rate is 100% (18/18), whereas in arm B, low ERG copy number patients responded better (8/11) compared to high copy number patients (7/11). Finally, the SMPR odds ratio remained close to 1.000 even for large copy number increase. Selective ERG responsive gene expression levels were determined in metastatic biopsies and will be associated with clinical endpoints.
Conclusions: Enzalutamide improved the likelihood of PSA remission in mHSPC and follow up is ongoing. Metastatic biopsy specimen analysis show that higher ERG copy number had a lower likelihood of PSA response with ADT and may serve as a prognostic or predictive marker, but further analysis is warranted.
Citation Format: Sreenivasa R. Chinni, Ulka N. Vaishampayan, Lance K. Heilbrun, Louie Semaan, Daryn Smith, Dipenkumar Modi, Paul Monk, Shiela Tejwani, Guru Sonpavde, Kimberlee Dobson, Brenda Dickow, Elisabeth Heath, Joseph Fontana, Micheal L. Cher. Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-309