Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy (ADT) vs. Dose Escalated Radiation Therapy and Enhanced ADT With TAK-700 for Men With High-Risk Prostate Cancer (NRG Oncology/RTOG 1115)
International Journal of Radiation Oncology Biology Physics
Purpose/Objective(s)RTOG 1115 was a randomized phase III trial evaluating the addition of orteronel (TAK-700), a novel CYP17A1 inhibitor, to dose escalated radiation plus ADT in men with high risk, localized prostate cancer. Originally designed to evaluate overall survival, the trial was halted early due to discontinuation of orteronel development in prostate cancer. We report here the initial primary endpoint analysis.
Materials/MethodsThe study was designed to enroll 900 men with high-risk prostate cancer (Gleason 9-10, PSA > 20, or clinical stage T2 or higher with Gleason ≥ 8). Ultimately, 238 patients were enrolled (May 2012-Sept 2014), and randomized 1:1 to receive standard therapy (Arm A), or standard therapy plus two years of twice daily orteronel (Arm B). Radiation therapy entailed dose-escalated external beam radiation (EBRT) to the prostate and pelvis to 45 Gy in 25 fractions, followed by a boost to 79.2 Gy using EBRT or either HDR or LDR. The analysis plan was reframed around detecting a reduction in rate of a composite biochemical failure endpoint (Phoenix biochemical failure, local/regional or distant disease, or salvage ADT). With 238 patients enrolled and followed, the study would have 70% power to detect a 40% decrease in the composite failure primary endpoint after 70 events had occurred.
Results231 patients were evaluable for efficacy and toxicity, 115 in Arm A and 116 in Arm B, and median follow up was 6.2 years. Grade 3 adverse events were observed in 35% and 60% of men in Arm A and B, respectively, with most common being urinary or gastrointestinal disturbance. Time to grade 3 adverse event was significantly faster in Arm B (log rank P value < 0.001). There were four deaths due to adverse events, three of which were in Arm A, and all were deemed unlikely related to treatment. Notably, only 29% of men in Arm B received 80% or more of the planned dose of orteronel due to a variety of factors that impacted drug tolerability. With respect to the primary outcome, patients did well overall with 6-year failure rates of 22.5% and 16.1%, respectively, in Arms A and B (hazard ratio [HR] 0.83, 95% CI 0.47-1.48). By Phoenix definition, PSA failure was only 18.4% and 12.1% in Arms A and B through 6 years. Distant failure occurred in 10.0% and 4.0% of patients (HR 0.71, 95% CI 0.29-1.75). Quality of life outcomes will be reported separately. While all efficacy trends favored the experimental arm, due to the small number of patients and events none of the differences between arms achieved statistical significance.
ConclusionThe addition of orteronel to dose escalated RT and ADT did not result in statistically significant improvement in efficacy outcomes, although results were limited by early termination of accrual and impaired drug tolerability. Intensification of hormonal therapy with better tolerated novel agents remains an appealing strategy for the treatment of high-risk localized prostate cancer.
Michaelson D, Dignam JJ, Hamstra DA, Bachand F, Master V, Bruner DW, et al. Phase III trial of dose escalated radiation therapy and standard androgen deprivation therapy (ADT) vs. dose escalated radiation therapy and enhanced ADT with TAK-700 for men with high-risk prostate cancer (NRG Oncology/RTOG 1115). Int J Radiat Oncol Biol Phys. 2022 Nov 1;114(3 Suppl):S67-S68. doi:10.1016/j.ijrobp.2022.07.458.