Long-term ADT Added to RT Improves Outcomes in Prostate Cancer

For men with prostate cancer who undergo a radical prostatectomy and postoperative radiotherapy, the addition of androgen deprivation therapy (ADT) for 24 months improves outcomes, more so than taking ADT for 6 months.

The findings come from the RADICALS-HD trial, which has been running for 15 years in four countries: the United Kingdom, Denmark, Canada, and Ireland.

The results show that ADT given for 24 months was superior to ADT given for 6 months in improving metastasis-free survival (MFS, 72% vs 78% at 10 years) and also delayed the time to salvage ADT (hazard Ratio (HR), 0.73).

However, the longer duration of ADT did not improve overall survival (HR, 0.88).

Dr Chris Parker

"Generally speaking, men who are having postoperative radiotherapy for prostate cancer usually do well and do not develop metastasis in 10 years," said lead author Chris Parker, MD, consultant clinical oncologist at The Royal Marsden NHS Foundation Trust in London, UK. "But the addition of 2 years of hormone therapy is more effective than 6 months."

"Up until now, patients and doctors have had to depend on opinions to choose whether or not to add hormone therapy to radiotherapy," he commented. These new results will help doctors and patients in the future to make an evidence based decision, he added.

The findings were presented at a Presidential Symposium during the European Society for Medical Oncology (ESMO) Congress 2022.

The RADICALS protocol was designed as a single clinical trial protocol, comprised of two separate cohorts. The first cohort, called RADICALS-RT, addressed the timing of radiotherapy for men who had recently undergone a radical prostatectomy, and compared adjuvant vs salvage radiotherapy.

The current results come from the RADICALS-HD part of the trial, which was a three-way comparison of 0 months vs 6 months vs 24 months of ADT.

"The objectives of the trial were to test the efficacy of adding hormone therapy to postoperative radiotherapy and also to compare short-term to long-term therapy," said Parker.

No Benefit for Short-term ADT

Parker and colleagues randomly assigned 2839 postoperative patients who had not yet begun receiving radiotherapy to one of three groups: no ADT (none), 6 months of ADT (short) or 24 months of ADT (long). The median age of the patients was 66 years, with 23% of patients having stage pT3b/T4 cancer and 20% with a Gleason score of 8-10. Mean prostate-specific antigen (PSA) before beginning radiotherapy was 0.22 ng/ml.

The primary endpoint was metastasis-free survival (MFS), and secondary endpoints included time to salvage ADT and overall survival.

Within this cohort, 1480 patients were included in the "None-vs-Short" assessment and 1523 patients in the "Short-vs-Long." The authors note that while the study groups were balanced within each comparison, the risk factors were more favorable in None-vs-Short as compared to Short-vs-Long.

At a median follow up of 9 years, 6 months of ADT did not improve MFS (based on 268 MFS events) as compared with no ADT (HR 0.89; 79% vs 80% event-free at 10 years). Although time to salvage ADT was delayed (HR, 0.54), overall survival was not improved (HR 0.88).

In the Short-vs-Long cohort, treatment with ADT for 24 months improved MFS (based on 313 MFS events; HR, 0.77). Time to salvage ADT was delayed but overall survival was also not improved.

"There was no improvement for the addition of 6 months of ADT, but there was a benefit for short- vs long-term," said Parker. "Metastasis free survival was improved by 23%."

He noted that given these results, patients will still make individualized decisions regarding their treatment options postoperatively. "Some will want to minimize toxicity and may decide that radiotherapy alone is a pretty good treatment," Parker said. "On the other hand, there are those who want to maximize the efficacy of treatment, and I think they will choose 2 years of hormone therapy with their radiotherapy and be willing to put up with the adverse effects."

He added that based on these results, it may become less common in the future to use 6 months of hormone therapy.

Interpreting the Results

Approached for comment on the new data, David J. Byun, MD, radiation oncologist, NYU Langone Perlmutter Cancer Center, New York City, explained that the current understanding of the role of ADT in postoperative settings is guided by RTOG 9601, GETUG-AFU 16, and SPPORT trials.

"However, the role and optimal duration of ADT continue to remain controversial, especially in the early salvage setting," said Byun, who was not involved with RADICALS-HD. "With a median pre-treatment PSA of 0.22 ng/ml, RADICALS-HD is an adjuvant/early salvage radiotherapy trial interrogating the need for and optimal duration of ADT with a primary endpoint of metastasis-free survival. While 3-way randomization was preferred, the majority of the patients were randomized to no ADT vs 6 months ADT or 6 months ADT vs 24 months ADT, limiting the ability to compare no ADT to 24 months of hormone therapy adequately."

He noted that in evaluating the results of no ADT vs short ADT randomization, "RADICALS-HD appears to reinforce the notion that early salvage radiation therapy may not necessitate the addition of short-term ADT other than to delay time to detection of biochemical progression in most patients."

"That is to say, 6 months of ADT may not confer clinically meaningful survival benefits for patients with low levels of PSA where the extent of disease likely remains local," said Byun, but he added that the results of the subgroup analysis of pre-RT PSA level stratification were not available at the time he reviewed the data.

"Interpreting results from short- vs long-term ADT randomization would require further contextualizing patient characteristics," Byun continued. "For example, how specifically were risk factors less favorable compared to none-vs-short group, what was the median pre-RT PSA, what percentage was treated with GnRH [gonadotropin-releasing hormone] agonist, and what percentage of patients had persistent PSA elevation postoperatively?"

In a discussion of the paper, Silke Gillessen, MD, PhD, director of the Oncology Institute of Southern Switzerland and head of Department of Medical Oncology, Bellinzona, Switzerland, emphasized that the key question is who should receive ADT. "The real question is also how to individualize therapy," she said.

"One approach is genomics and it has been shown that having a higher genomics classifier score has been associated with more benefit of hormone treatment to salvage radiotherapy," said Gillessen. "But the difference was not statistically significant and the test is expensive."

Another approach that is more promising is the use of artificial intelligence (AI) based on pathology slides. "As these tests are clinically validated and become more widely available, we also have to consider a combination of clinical factors."

Gillessen added that a meta-analysis of subgroups from relevant clinical trials, including RADICALS HD, may help characterize the importance of clinical factors and combinations of them.

The study was funded by Cancer Research UK, Medical Research Council, and the National Institute for Health and Care Research's Clinical Research Network (NIHR CRN).

Parker reports relationships with Bayer, Janssen, Myovant, ITM Radiopharma, and AAA. Co-author C. Catton reports financial interests with AbbVie and TerSera Corp. Co-author H. Payne reports financial interests with AstraZeneca, Astellas, sanofi-aventis, Ferring, Bayer, and Novartis. The other co-authors reported no relevant financial relationships.

2022 Congress of the European Society for Medical Oncology (ESMO). Abstract LBA9. Presented September 12, 2022.

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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