ADT Timing Considerations Set Out For Relapsed PSA Patients

Immediate androgen-deprivation therapy may improve long-term overall survival at a small quality of life cost in men with rising prostate-specific antigen after curative treatment or incurable disease

medwireNews: Study findings shed light on the benefits and risks of immediate versus delayed androgen deprivation therapy (ADT) for men with prostate cancer who have rising prostate-specific antigen (PSA) after attempted curative treatment or who are unsuitable for curative therapy.

“To our knowledge this is the first randomised trial to provide evidence of the impact of the timing of androgen-deprivation therapy in men with prostate cancer with a PSA relapse”, report Gillian Duchesne, from Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia, and co-workers.

“It provides a benchmark for the survival rates of men diagnosed with this disease stage, which was not previously available, and indicates the effects on survival, disease progression, development of complications, toxicity of treatment, and quality of life.”

Five-year overall survival (OS) was significantly higher for the 142 patients given immediate ADT, at 91.2% versus 86.4% for the 151 men whose treatment was delayed for at least 2 years in the absence of symptomatic or metastatic disease, or who had a PSA doubling time of less than 6 months.

However, the OS curves did not separate until after 5 years, with men given immediate treatment significantly more likely than patients given delayed ADT to survive for 6 years (85.6 vs 76.4%) and 7 years (81.0 vs 65.5%), although the researchers acknowledge that as median follow-up was just 5 years, “relatively few men were evaluable in later years”.

Men given immediate ADT also had a significantly longer time to both local and distant progression than the delayed treatment group, as well as a significantly reduced risk of developing castration resistance from date of beginning therapy.

The researchers believe these findings may reflect “the development of clonal resistance in the untreated patient as disease progresses, with reduction of treatment responsiveness and effectiveness in overt metastatic disease.”

At least one adverse event was reported by 78% of men given immediate treatment versus 47% of those in the delayed treatment group, with most ADT-related side effects of grade 1 or 2. Just 10% of patients given immediate ADT had a grade 3 event, most commonly hot flush, erectile dysfunction, fatigue and gynaecomastia.

More than 90% of patients completed quality of life questionnaires; after 2 years patients given immediate treatment experienced a “small but clinically important” decrease in quality of life whereas delayed treatment patients had a “clinically trivial” loss, indicating that there may be “a small trade-off for any benefit that could be provided by immediate therapy”, the researchers comment.

“Survival might be prolonged with immediate treatment, but there is little gain for the first few years, and more than half of men with either strategy will still be alive after 8 years”, Gillian Duchesne et al summarise for clinicians discussing management strategies with their patients.

However, they note that just 41% of men in the delayed treatment group did not reach a trigger for ADT treatment, dropping to 21% of men who had incurable prostate cancer. And say that such patients should be cautioned that in light of risk factors predicting a poor prognosis, ADT is only likely to be delayed by approximately 12 months.

“Despite the increasing sensitivity of new imaging modalities that can now show metastatic disease at an earlier stage than previously, which will stage-shift men from biochemical relapse only to overt disease, the question of when to introduce therapy remains valid, and might be partly addressed by the results of this trial”, the authors conclude in The Lancet Oncology.

Reference

Duchesne GM, Woo HH, Bassett JK, et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol 2016; Advance online publication 4 May. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00107-8

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