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Chris Wallis: Hello and thank you for joining us for our UroToday Journal Club discussion. Today, we're discussing a recent publication from the DART 01/05 study, high-dose radiotherapy and risk-adapted ADT in localized prostate cancer, 10-year results of a phase three randomized controlled trial. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation for this work, which was recently published in the Lancet Oncology.

Radiotherapy is, as most will know, a standard treatment option in patients with localized prostate cancer. With conventional dosing of radiotherapy, the addition of ADT improves biochemical recurrence and overall survival. However, dose escalation has also been shown to be beneficial. So thus, there's an interest in the role of ADT in the context of dose escalation. Five year results of the DART 01/05 study, which is a Spanish phase three randomized control trial comparing long ADT, 24 months of adjuvant ADT following four months of neoadjuvant and concurrent ADT to short-term, four month ADT showed an improved biochemical recurrence, metastasis, and overall survival data. An amendment proposed in 2013 added follow-up to 10 years based on the overall indolent nature of prostate cancer.

So this study is, as alluded to before, an open-label, multicenter, phase three randomized controlled trial performed at 10 university hospitals in Spain. It also has included men, 18-years and older with histologically confirmed prostate cancer, who had intermediate or high-risk disease, that had PSAs less than 100, an Karnofsky performance status of 70 or greater, and a life expectancy of at least 5 years. Patients were excluded if they had T4 disease, clinical evidence of regional nodal involvement or distant metastases, if they'd had prior pelvic radiotherapy or surgery, if they'd been placed on neoadjuvant ADT for more than three months, or if they had received concurrent chemotherapy.

In the pre-treatment evaluation, all patients were clinically staged, underwent a transrectal ultrasound, CT scan, and bone scan. They were, on the basis of these results as well as their biopsy and PSA results, stratified into intermediate and high risk groups, as you can see here in keeping with NCCN criteria. Patients were randomized in a one-to-one fashion to receive either four months of neoadjuvant and concomitant ADT with high dose radiation or the same neoadjuvant and concomitant ADT and radiation with an additional 24 months of adjuvant androgen deprivation. Radiotherapy was delivered with 3D conformal radiation with a minimum dose of 76 Gray. 34 included patients received IMRT rather than 3D conformal. The target was the prostate seminal vesicles with elective nodal radiation performed at the discretion of the treating physician in their center.

ADT was administered with subcutaneous goserelin, which was started two months prior to radiation, and continued for two months during radiation. Oral anti-androgens were also used in the first two month period, and in those randomized long-term ADT, the same treatment was continued out for an additional 24 months.

The primary outcome was disease-free survival, biochemical disease-free survival at five years, and this has already been reported. Secondary outcomes include overall survival, metastasis-free survival, cancer specific survival, and late GU and GI toxicities. In this 10-year analysis, the authors assess overall survival, cancer specific survival, metastasis-free survival, and biochemical failure free survival.

Biochemical failure free survival is defined as the time from randomization to a PSA two above nadir, death from any cause or censoring. Metastasis-free survival is defined as the time from randomization to document of metastasis or death, and patients who receive salvage therapies were censored at the time of the initiation of these treatments. Cancer specific survival in this study was defined as the time from randomization to death from prostate cancer, or cancer treatment related complications, or death due to an unknown cause in patients who had active cancer.

In terms of analysis, the authors powered the study based on an estimated five year biochemical failure free survival of 60% in the high risk group and 70% in the intermediate risk group. They hypothesized that the addition of adjuvant ADT increased these to 75 and 85% respectively, and this resulted in a planned sample size of 353 patients. In this analysis, all outcomes are secondary and they perform the analyses according to a pre-specified plan and used the intention to treat principle. Overall survival was assess using Kaplan Meier curves and a log-rank test with Cox Proportional Hazards models. The other endpoints were assessed using competing risks models with finding Gray with regression. Multivariable analyses included, age, stage, PSA, Gleason score, treatment group, radiation dose, the use of pelvic radiation, and PSA nadir as covariance. The authors finally performed stratified analysis between those with intermediate or high risk disease. I'm now going to hand it over to Zach to walk us through the results of DART 01/05.

Zachary Klaassen: Thanks so much, Chris, for that introduction. This is the figure looking at the trial profile. This figure shows that 498 patients were assessed for eligibility. Ultimately 362 were enrolled and 355 were randomly assigned, including 178 to short-term ADT and 177 to long-term ADT.

This table looks at the baseline and treatment related characteristics. As you can see here, long-term ADT on the right and short-term ADT to the left. For both arms, extremely long fall, nearly 10 years at 119.4 months. Median age was comparable between the groups of nearly 71 to 72 years. In terms of T-stage, we see the most common T-stage was T2 disease at just over 50%. Median PSA for each of these groups was 11. Most common Gleason score for these patients was Gleason four plus three for the short-term ADT and Gleason three plus four for the long-term ADT. With regards to prostate radiotherapy dose, nearly three quarters of these patients received more than 78 Gray of radiotherapy. In terms of salvage treatment, 10% of the short-term ADT and 5% of the long-term ADT had androgen deprivation therapy as a salvage treatment.

So the next several slides we'll look at Kaplan Meier curves and the color scheme will be the same for all of these curves. Long-term ADT will be in blue, short-term ADT will be in red. This first slide looks at biochemical disease free survival in the overall population. The 10-year rate of BDFS was 70.2% in the long-term ADT arm and 62.3% in the short-term arm, with a non significant hazard ratio of 0.84. This looks at metastasis disease-free survival in the overall population with a 10-year MFS rate in long-term ADT arm of 76% and 70.9% in the short-term ADT arm. Again with a not statistically significant hazard ratio of 0.90. This looks at the overall survival in the overall population I for 10-year rate of OS in the long-term ADT arm was 78.4% compared to 73.3% in the short-term ADT with a hazard ratio of 0.84 and 95% confidence interval of 0.55 to 1.27.

Looking now at the high risk population, this is biochemical disease-free survival with a 10-year rate of BDFS of 67.2% in the long-term arm and 53.7% in the short-term arm with a hazard ratio of 0.90 and a 95% confidence interval of 0.49 to 1.64. This looks at metastasis disease-free survival in this high risk population with a 10-year rate of MFS of 76.6% in the long-term arm and 65% in the short-term arm and a nonsignificant hazard ratio of 0.89. Finally, this looks at the overall survival in the high risk population. Again, no benefit for long-term ADT, the 10-year rate of overall survival of 78.5% and a short-term ADT arm of 67.0%. Although no statistically significant benefit, we do see that the hazard ratio of 0.58 with a confidence interval of 0.33 to 1.01. So this plot looks at all of these previous slides, sort of summarized into this one Forest Plot, and again, we see no benefit across any of these outcomes. Although I did highlight the high risk overall survival patients with a hazard ratio of 0.58 and a 95& confidence interval of 0.33 to 1.01.

In terms of adverse events, basically very comparable between the two arms with regards to grade three and grade four adverse events. We see most commonly of grade three is urinary adverse events at 7% in each of these arms. So discussion points from the study, the phase three DART 01/05 trial is the first study to evaluate the optimal duration of ADT in patients with intermediate and high risk localized prostate cancer treated with high-dose radiotherapy. At 10-years of follow up, the results of the updated analysis could not support the five year statistically significant survival improvement with long-term versus short-term ADT. The authors offered several possible explanations for the discrepancy.

First of all, the competing risks of non prostate cancer death in a relatively old population. Secondly, the use of salvage hormone therapy may have delayed or prevented occurrence of distant metastases and prostate cancer death. Third, the potential synergistic or cooperative benefit of high-dose radiotherapy in both groups may decrease the advantage obtained with long-term ADT compared to a short-term ADT. Final point in the discussion, DART 01/05 support intermediate risk patients not receiving long-term ADT.

So in conclusion, although this study could not confirm the statistically significant five year benefit of long-term ADT at 10-years, these results showed a consistent, absolute, and clinically relevant benefit of long-term versus short-term ADT. This included a 12% benefit in biochemical disease-free, metastasis-free, and overall survival in patients with high risk prostate cancer. Finally, these findings are probably due to the competing risks of non prostate cancer death in an aging population with a high life expectancy, leading the curves to converge at 10-years of follow up. Thank you very much for your attention. We hope we enjoyed the UroToday Journal Club discussion on the DART 01/05 trial.