medwireNews: A meta-analysis has confirmed the benefit of adding androgen deprivation therapy (ADT) to radiotherapy for localized prostate cancer, and a cohort study has provided guidance on the optimal duration of the therapy.
Add-on ADT improves outcomes
The meta-analysis, published in The Lancet Oncology, included individual patient data on 10,853 participants of 12 trials evaluating the use and/or prolongation of ADT in men with localized prostate cancer undergoing definitive radiotherapy.
Data from seven comparisons across six trials (n=5136) showed that supplementing radiotherapy with ADT significantly improved metastasis-free survival (MFS), at a hazard ratio (HR) of 0.83. The estimated MFS rates at 10 years were 61% with ADT and 52% without ADT.
Adding ADT to radiotherapy also significantly improved overall survival (OS), at an HR of 0.86 compared with radiotherapy alone, and estimated 10-year OS rates of 65% and 57%, respectively.
The prolongation of adjuvant ADT, from a median of 5 to 28 months across four trials (n=3774), was also associated with a significant improvement in both MFS and OS, with respective HRs of 0.84 and 0.85. The estimated 10-year MFS rates with long- and short-term ADT were 55% versus 47%, while the corresponding OS rates were 63% and 57%.
By contrast, three trials (n=2213) evaluating the prolongation of neoadjuvant ADT, from a median total duration of 4 months to 8 months, found no significant MFS or OS benefit of extending the ADT course.
Daniel Spratt (Case Comprehensive Cancer Center, Cleveland, Ohio, USA) and colleagues note that the findings regarding ADT use and adjuvant and neoadjuvant ADT extension were similar for the endpoints of biochemical recurrence and distant metastasis rates.
Furthermore, “the treatment effects of each intensification strategy were not significantly affected by radiotherapy dose, NCCN [National Comprehensive Cancer Network] risk group, or patient age,” they highlight.
The team concludes that these results “provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer,” but adds that “the magnitude of the benefit could vary and shared decision making with patients is recommended.”
Identifying the optimal duration of ADT
The second study drew on databases from 16 US tertiary referral centers to identify 2935 men with high-risk prostate cancer as per the NCCN criteria who received definitive treatment with high-dose external beam radiotherapy (EBRT), either alone or with a brachytherapy boost, in 2000–2014.
Amar Kishan (University of California, Los Angeles, USA) and co-researchers divided the cohort into three groups based on the length of ADT – less than 6 months (short-term), 6 to less than 18 months (intermediate-term), and 18 months or more (long-term) – and found a significant interaction “between treatment type and the effect of ADT duration” for distant MFS and OS.
Specifically, among patients who received EBRT alone, long-term ADT use, but not intermediate-term use, was associated with significant improvements in both distant MFS and OS relative to short-term use, at HRs of 0.44 and 0.45, respectively.
Long-term use also significantly improved distant MFS and OS compared with intermediate-term ADT, with respective HRs of 0.49 and 0.50.
In the EBRT plus brachytherapy group, both the long and intermediate durations of ADT correlated with significant improvements in outcomes relative to the short duration, at HRs for distant MFS of 0.34 and 0.42, respectively, and for OS of 0.30 and 0.43.
But long-term ADT did not significantly improve distant MFS versus intermediate-term use in these patients and was linked to significantly worse OS (HR=1.44).
The findings were supported by an analysis of individual patient data from the phase 3 RADAR trial that investigated 6 versus 18 months of ADT given alongside EBRT alone or with brachytherapy, as well as by a comparison of the RADAR data with that of the participants who received 28 months of ADT plus high-dose EBRT in the phase 3 DART study.
Finally, the researchers used adjusted natural cubic spline analysis to identify the optimal duration of ADT as 26.3 months for men receiving EBRT alone and 12.0 months for those treated with EBRT plus brachytherapy.
And they conclude in JAMA Oncology: “Ongoing and future trials will help clarify whether predictive biomarkers can aid in selecting optimal ADT durations; in the interim, individual patient meta-analyses that consider ADT duration data from various relevant trials may be the best available guidance on optimal ADT duration.”
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Lancet Oncol 2022; doi:10.1016/S1470-2045(21)00705-1
JAMA Oncol 2022; doi:10.1001/jamaoncol.2021.6871