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Androgen suppression benefits men with rising PSA after prostatectomy
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The addition of short-term androgen suppression to salvage radiotherapy significantly extended PFS among men with rising PSA concentrations after radical prostatectomy, according to a randomized, multicenter, open-label phase 3 trial.
“Radical prostatectomy remains one of the standard treatments for localized prostate cancer in men younger than 70 years,” Christian Carrie, MD, chief of the department of radiotherapy at Centre Léon Bérard in Lyon, France, and colleagues wrote. “However, 30% to70% of men have biochemical relapse at 5 years, depending on their initial prognosis.”
Prior research showed salvage radiotherapy — the standard of care for men with increased PSA concentration after radical prostatectomy — resulted in a 75% reduction in risk for distant metastases and a 20% reduction in the need for androgen ablation therapy.
However, fewer than half of patients remain free of biochemical relapse 5 years after salvage radiotherapy alone, according to study background.
Carrie and colleagues evaluated the effect of adding short-term androgen suppression to salvage radiotherapy for men with rising PSA (0.2 to <2) after radical prostatectomy but no evidence of clinical disease. The analysis included 743 men (median age, 67 years). Researchers randomly assigned 369 patients to radiotherapy plus goserelin, and the other 374 patients received radiotherapy alone.
PFS served as the primary endpoint. Secondary endpoints included OS, toxicities, time to nadir PSA, metastasis-free survival and changes in quality of life.
After median follow-up of 63 months (interquartile range, 56-75), a significantly higher percentage of patients assigned the combination appeared free of biochemical or clinical progression (80% vs. 62%; HR = 0.5; 95% CI, 0.38-0.66).
Multivariate analysis revealed several factors prognostic for disease progression, including PSA concentration at the time of radiotherapy, surgical margin status, PSA doubling time at relapse and seminal vesicle status.
Researchers observed the PFS benefit with the combination among patients with low-risk and high-risk disease.
Median OS was 58 months (IQR, 53-64) in the entire cohort, 58 months (IQR, 57-79) among those assigned the combination and 56 months (IQR, 51-62) among those assigned to radiotherapy alone.
Researchers reported a comparable 5-year OS rate between the two groups (96% vs. 95%; HR = 0.7; 95% CI, 0.4-1.2).
Eight percent of patients assigned goserelin experienced grade 2 or worse adverse events. The most frequent acute adverse events among those assigned goserelin were hot flushes (8%) sweating (1%) or both. Three patients experienced grade 3 hot flushes and one experienced grade 3 sweating.
Rates of late genitourinary events (combination, 67%; radiotherapy alone, 70%) and grade 3 or worse genitourinary events (7% vs. 8%) were comparable between treatment groups.
No treatment-related deaths occurred.
“The fact that there was no dierence in radiation-related late adverse events between treatment groups supports the observation that no dierence in health-related quality of life was seen between the two groups,” Carrie and colleagues wrote.
The researchers acknowledged the study was limited by only recording first progression.
“Salvage radiotherapy combined with short-term androgen suppression significantly improved 5-year progression-free survival compared with salvage radiotherapy alone and can delay the need for more aggressive therapy,” Carrie and colleagues wrote. “Longer follow-up is needed to establish the eect of this therapeutic strategy on overall survival.” – by Kristie L. Kahl
Perspective
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Rahul Tendulkar, MD
Salvage radiation therapy is the standard of care for most patients with a rising PSA after radical prostatectomy. GETUG-AFU 16 is the first published randomized trial to report the impact of adding androgen deprivation therapy (ADT) to salvage radiotherapy. Importantly, this study was conducted in a contemporary era using conformal radiation therapy techniques and luteinizing hormone-releasing hormone agonist therapy, and salvage therapy was initiated at a lower PSA level (median, 0.3 ng/ml) than historically done. The addition of a short course of ADT to salvage radiotherapy significantly reduced by half the risk for subsequent clinical or PSA recurrence, and virtually all subgroups benefited similarly. Treatment was well tolerated in both arms, with no significant long-term toxicities from combined-modality therapy. There was no observed OS difference, as longer follow-up time is needed.
A similar study the Radiation Therapy Oncology Group (RTOG) 9601 trial was recently presented in abstract form. RTOG 9601, for which median follow-up was more than 12 years, demonstrated that 2 years of ADT improved OS when added to salvage radiation therapy. Unlike the GETUG-AFU trial, RTOG 9601used oral antiandrogen therapy and techniques of radiotherapy that are considered outdated by modern standards. It also included patients with higher baseline PSA levels than the GETUG-AFU 16 trial.
GETUG-AFU 16 and RTOG 9601 have provided the first randomized trial evidence that the addition of ADT to salvage radiotherapy can improve clinical outcomes in men with a detectable PSA after radical prostatectomy. Determining exactly which subsets of patients may derive the greatest benefit from combined modality therapy will require further investigation.
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