Men with high-risk localized prostate cancer had a significant survival benefit when treated with a more intensified regimen of dose-escalated radiation therapy plus long-term androgen-deprivation therapy (ADT) vs standard radiation therapy plus ADT, according to long-term follow-up from the GETUG-AFU 18 trial, presented at the 2024 ASCO Genitourinary Cancers Symposium.1
With a median follow-up of 9.5 years, the 10-year overall survival rate increased from 65.9% with standard-dose (70 Gy) radiation therapy plus 3 years of ADT to 77% with higher dose (80 Gy) radiation therapy plus ADT. At 10 years, cancer-specific and progression-free survival improved significantly with dose-escalated radiation therapy. These benefits were achieved with no apparent increase in late genitourinary and gastrointestinal toxicities with the higher dose of radiation and no reported detriment to quality of life.
Christophe Hennequin, MD
“Even if we use long-term ADT, high-dose radiation therapy improved progression-free survival, cancer-specific survival, and overall survival in high-risk prostate cancer without increasing toxicity,” said lead author Christophe Hennequin, MD, of Saint-Louis Hospital, Paris. “However, intensity-modulated radiation therapy [IMRT] is required to obtain these results. We now have level 1 evidence that high-dose radiation therapy with long-term ADT must be a standard of care in high-risk prostate cancer,” he stated.
“Several trials have evaluated the role of dose-escalated radiation therapy in prostate cancer, but none has demonstrated improved overall survival. Long-term ADT improved overall survival, and even with higher-dose radiation therapy, it seems that long-term ADT is needed,” Dr. Hennequin commented.
Study Details and Results
Designed 20 years ago, GETUG-AFU 18 enrolled 505 patients with high-risk localized prostate cancer from 25 French centers from June 2009 to January 2013. High risk was defined as one of the following features: prostate-specific antigen (PSA) of 20 ng/mL or higher or Gleason score of 8 or higher. All patients received 3 years of ADT and were randomly assigned to receive 80 Gy (high dose) or 70 Gy (standard dose) of radiation. Dr. Hennequin emphasized that significantly more patients in the 80-Gy arm were treated using IMRT: 80.6% vs 58.6%, respectively (P < .001). “There was a clear improvement in survival with the dose-escalated regimen at 5 and 10 years,” he said.
The primary endpoint was 5-year progression-free survival, which was met by the dose-escalated radiotherapy arm (91.4% vs 88.1% for standard-dose radiotherapy). Secondary endpoints included cancer-specific survival, overall survival, and toxicity.
The updated analysis reported a 10-year progression-free survival rate of 83.6% vs 72.2%, respectively, for a 44% relative risk reduction in the likelihood of disease progression or death (P = .0005). The 10-year rate of cancer-specific survival was 95.6% with 80 Gy and 90.0% with 70 Gy, for a 52% risk reduction (P = .0090). The 11-point absolute difference in 10-year overall survival reflected a risk reduction in the likelihood of death of 39% (P = .0039).
The incidence rates of grade ≥ 2 and ≥ 3 genitourinary toxicity were 19.9% and 3.2% in the 70-Gy arm and 20.6% and 2.0% with dose-escalated radiotherapy, respectively. “There was no difference in late toxicity in both arms nor in quality of life between the two arms,” Dr. Hennequin said.
Expert Point of View
Neha Vapiwala, MD, FACR, FASTRO, FASCO
Invited discussant of the GETUG-AFU 18 trial, Neha Vapiwala, MD, FACR, FASTRO, FASCO, from the Perelman School of Medicine, Philadelphia, noted that radiation therapy and androgen-deprivation therapy (ADT) have biologic synergy. “They are co-dependent with complex cytotoxic interactions,” she noted.
“GETUG-AFU 18 helps us look at the sole contribution of the dose escalation of radiation in the context of long-term ADT, taking that as the de facto standard for high-risk patients,” she said. “With a primary endpoint of 5-year biochemical or clinical progression-free survival, not only are these curves statistically significantly separated, but they remained so over the entire duration of follow-up. Perhaps even more remarkable are the secondary endpoints of prostate cancer–specific survival and overall survival, which were statistically significantly improved,” Dr. Vapiwala emphasized. The results of GETUG-AFU 18 are “practice-affirming for many, perhaps practice-changing for some who are not already offering dose-escalation through some form, including hypofractionated radiation regimens and brachytherapy.”
Additional Benefit Confirmed
“This important work by Dr. Hennequin and colleagues provides us with level 1 evidence that in patients with high-risk, clinically node-negative, nonmetastatic prostate cancer receiving long-term ADT, escalating the radiotherapy dose using modern techniques adds clinical value without adding appreciably to the treatment toxicity,” Dr. Vapiwala stated.
She continued: “In patients with high-risk prostate cancer, there is significant concern for both locoregional and micrometastatic disease; thus, the combination of longer-term ADT and radiotherapy is a standard-of-care treatment option. The question is whether there is additional benefit to increasing the radiotherapy dose, and that is what GETUG-AFU 18 helped to answer for us. Importantly, this benefit is not just in terms of the prostate-specific antigen levels, but also cancer-specific and overall survival.”
Dr. Vapiwala concluded: “These data strongly suggest that delivering more radiotherapy and improving control of local disease can independently increase the odds of being and staying free of cancer and of spread to other locations. Future areas of research include developing tools to determine patient subgroups for whom decreased duration of ADT and/or decreased radiotherapy dose can still achieve excellent results, for more refined and tailored approaches.”
DISCLOSURE: GETUG-AFU 18 was supported by the French National Cancer Institute, the French National Cancer League, and AstraZeneca. Dr. Henequin reported financial relationships with Astellas, Bayer, Ipsen, and AstraZeneca. Dr. Vapiwala reported no conflicts of interest.
REFERENCE
1. Hennequin C, Sargos P, Roca L, et al: Long-term results of dose escalation (80 vs 70 Gy) combined with long-term androgen deprivation in high-risk prostate cancers: GETUG-AFU 18 randomized trial. 2024 ASCO Genitourinary Cancers Symposium. Abstract LBA259. Presented January 25, 2024.
