ASCO 2017: The benefit of combining docetaxel to androgen deprivation therapy in localized and metastatic castration-sensitive prostate cancer as predicted by ERG status: An analysis of two GETUG phase III trials

Chicago, IL (UroToday.com) Metastatic prostate cancer (mPCa) used to be defined by the receipt of chemotherapy (docetaxol) or not. However, with the introduction novel AR axis therapies such as enzalutamide and abiraterone, among others, the entire paradigm of mPCa has changed. While androgen-deprivation therapy (ADT) had remained the standard first line therapy for newly diagnosed mPCa, and chemotherapy and the AR targeting therapies were held for patients with metastatic castration-resistant disease (CRPC), the findings of recent studies have shifted chemotherapy to a first-line therapy in conjunction with ADT.1 Three large trials (CHAARTED, GETUG-15, STAMPEDE) demonstrated survival benefit with combination docetaxol and ADT for M1 hormone-naïve prostate cancer. In the GETUG-12 study, benefit in the form of longer progression-free survival (PFS) was also identified in high-risk localized M0 prostate cancer patients.

As docetaxol chemotherapy is not a benign medication and, as the authors note, it is unlikely that all patients derive benefit, selection criteria are needed to better select patients that are likely to benefit. In this study, the authors hypothesize that TMPRSS2:ERG fusion status may be a potential selection criteria.

Pre-treatment prostate biopsy tissue was obtained from the GETUG-12 and GETUG-15 clinical trials, which assessed the role of docetaxol chemotherapy in conjunction with ADT in the setting of high-risk localized or metastatic PCa, respectively. Of the 413 GETIG-12 and 385 GETUG-15 patients, 255 and 79 samples were able to obtained, respectively. After assessing the presence of ERG, PTEN, Ki67 and Rb using immunohistochemistry, survival outcomes (recurrence-free survival) was assessed.

Patients from the GETUG-12 study were primarily cT3-4 (72%) and pN0 (73%). There was an even mix between Gleason <= 7 and >7 and PSA <= 20 and > 20. In the 79 GETUG-15 patients included, 61 (77%) were metastatic and 13 (16%) had visceral metastases.

ERG staining was positive in 88/191 (46%) and 33/79 (42%) pts with available tissue, respectively. In the GETUG 12 study, docetaxel-based chemotherapy was associated with improved RFS in ERG+ patients (HR = 0.55 [0.29-1.03]; 6-year RFS : 80% ADT+docetaxel vs 68% ADT alone), but not in ERG- patients (HR = 1.10 [0.66-1.85]; 6-year RFS 55% ADT+docetaxel vs 60% ADT alone). Similar findings were observed in GETUG 15, which was used as a validation set. The median RFS in the GETUG-15 study was 10.7 (6.5-14.3) and 18.8 (9.8-41) months in ERG+ patients receiving ADT alone or ADT+docetaxel, respectively, while it was 10.6 (4.8-25.3) and 13.2 (9.4-24) months in ERG- patients. Importantly, when the same analysis was repeated based on PTEN, Ki67 and Rb expression, no difference in patient outcome by docetaxel treatment was observed.

Limitations:
1. It is unclear why the authors chose to look at RFS in GETUG-12 and PFS in GETUG-15, especially without reporting the complementary results. If not significant, it should still be reported.
2. The samples obtained are a small portion of the original trial cohorts. Particularly the GETUG-15 trial cohort.

Based on this, the authors conclude that TMPRSS2: ERG fusion may serve as an important biomarker of docetaxol chemotherapy efficacy. However, as this is a retrospective study, and a significant portion of the patient samples were not available, a prospective randomized study is required to confirm these results.

Presented By: Shanna Rajpar, MD

Co-Authors: Alexandra Carmel, Zahira Merabet, Philippe Vielh, Stephanie Foulon, Francois Lesaunier, Remy Delva, Frederic Rolland, Frank Priou, Jean-Marc Ferrero, Nadine Houede, Loic Mourey, Christine Theodore, Ivan Krakowski, Laura Faivre, Muriel Habibian, Stephane Culine, Anne Chauchereau, Gwenaelle Gravis, Karim Fizazi

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

References:
1. Vale CL, Burdett S, Rydzewska LH, Albiges L, Clarke NW, Fisher D, Fizazi K, Gravis G, James ND, Mason MD, Parmar MK, Sweeney CJ, Sydes MR, Tombal B, Tierney JF; STOpCaP Steering Group.
Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016 Feb;17(2):243-56. doi: 10.1016/S1470-2045(15)00489-1. Epub 2015 Dec 21.
2. Fizazi K et al. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. doi: 10.1016/S1470-2045(15)00011-X. Epub 2015 May 28.