A major trial has demonstrated that lower risk prostate cancers do not fare better by adding 6 months of hormone treatment to radiotherapy following radical prostatectomy, compared with radiotherapy alone. On the other hand, adding 2 years of hormone treatment instead of 6 months only to radiotherapy (RT) did lead to better 10-year metastasis-free survival in men with a higher risk of recurrence.
The researchers involved in the trial said these “practice-changing” results could enable thousands of prostate cancer patients with higher risk cancer to benefit from improved treatment outcomes with longer courses of androgen deprivation therapy (ADT). At the same time, patients with lower risk cancer could be reassured that radiotherapy alone is effective following surgery, so avoiding the need for unnecessary hormone therapy and its side effects.
Trial chief investigator Chris Parker, professor of prostate oncology at the Institute of Cancer Research, London, told Medscape News UK that the take-home implications of the study were that "the use of hormone therapy with post-op RT has benefits and harms". He said that the trial results will help patients and their doctors make an informed decision about the duration of hormone therapy.
Shared decision-making, informed by the trial results, and by patient values regarding side effects of hormone therapy, should help front-line clinicians select which patients should be offered long-term ADT, he said.
The phase III RADICALS-HD trial results were simultaneously published in two papers in The Lancet.
Optimal Use and Duration of ADT Previously Uncertain
Around 7000 men with localised prostate cancer undergo prostatectomy each year. Around 2000 of them go on to have RT. There is strong evidence that adjuvant, short-course ADT improves metastasis-free survival when given with primary RT as initial treatment for intermediate and high-risk localised prostate cancer.
However, it was previously unclear if adjuvant ADT confers additional benefit if used with post-operative RT after radical prostatectomy, so one arm of the trial was designed to test this. The optimal duration of ADT in this situation is also uncertain, so the trial also tested 6 months compared with 2 years of ADT.
Between 2007 and 2015, 1480 post-prostatectomy participants from four countries were randomised to RT alone or RT plus 6 months' ADT, using either subcutaneous GnRH analogue injections or 12 bicalutamide monotherapy 150 mg daily. A further 1523 patients across five countries were randomised between 2008 and 2015 to either 6 months or 2 years of ADT. In both arms, participants were followed up for a median of 9 years.
Results showed that, among men with lower risk prostate cancer, 10-year metastasis-free survival was 79% with RT alone, compared with 80% with RT plus 6 months of ADT, an insignificant difference.
For men with a higher risk of recurrence, there was a clear benefit from ADT for 2 years compared with 6 months, with 10-year metastasis-free survival rates of 78% and 72% respectively.
The researchers concluded: "These data are not sufficient to recommend use of short-course ADT with post-operative RT." However: "For people who can accept the additional duration of adverse effects, long-course ADT should be offered with post-operative RT."
Information Should Help Compare Treatment Options
The trial was part-funded by Cancer Research UK, whose science engagement manager, Dr Anna Kinsella, told Medscape News UK: "Every year there are around 52,300 new prostate cancer cases in the UK. That's more than 140 every day. The more treatment options we have available, and the more we understand about the best ways to use them, the closer we are to more people living longer, better lives, free from the fear of cancer."
The researchers noted that current use of ADT post-prostatectomy is "variable", and that guidelines "make only weak recommendations". Parker said that he hoped that, as a result of the trial, "the use of ADT should now be based on knowledge of the benefits and harms of ADT". He added: "This is the first trial to compare short versus long ADT in this setting, and I expect that the guidelines will be modified to reflect this."
However, he cautioned that after 24 months of ADT, testosterone recovery may be delayed or incomplete – while it usually takes around 12 months, in some cases after prolonged treatment, testosterone may never recover. ADT adverse effects may include sexual dysfunction, metabolic syndrome, and osteoporosis.
More Research Needed on Long-Term Survival
The RADICALS-HD results will be included in the ongoing systematic review and meta-analysis DADSPORTÂ (duration of androgen suppression with post-operative radiotherapy) being conducted by the Medical Research Council Clinical Trials Unit at University College London, which will provide more data on overall survival, Parker said. His team's future work will focus on trying to predict who will benefit from ADT and who will not.
Commenting on the study for Medscape News UK, Dr Matthew Hobbs, director of research at Prostate Cancer UK, said: "As well as slowing or preventing cancer from spreading, androgen deprivation therapy can have serious negative impacts on a man’s physical and mental well-being – so it’s important that men and healthcare professionals weigh up the pros and cons of the treatment. These results will help inform those conversations, providing more robust evidence on which to base decisions. The crucial next step for this trial, and many others, is to ensure we learn as much as possible from the data and samples that have been collected to drive towards more precise and more personalised treatments, based on an understanding of which men benefit from the treatment and which men do not."
Â