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Immediate ADT may improve OS in men with prostate cancer, rising PSA
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Immediate initiation of androgen deprivation therapy improved OS among men with noncurable or PSA–relapsed prostate cancer, according to the results of a randomized phase 3 trial
ADT is offered to men who exhibit a rising PSA after curative therapy for prostate cancer, or who are deemed unsuitable for curative treatment. However, the ideal timing of ADT introduction is not known.
Peter R. Carroll
Gillian M. Duchesne, MD, radiation oncologist at Melbourne University’s Peter MacCallum Cancer Centre in Australia, and colleagues sought to determine whether immediate administration of ADT improved OS compared with delayed initiation.
The researchers evaluated data from 293 men with prostate cancer (PSA relapse, n = 261; noncurable disease, n = 32), whom they randomly assigned to immediate (n = 142) or delayed (n = 151) ADT.
Men assigned to the immediate intervention arm initiated ADT within 8 weeks of randomization. The researchers recommended that men in the delayed therapy arm initiate treatment at least 2 years after assignment, unless symptoms or metastases developed or PSA doubling times decreased to 6 months or less.
Treatment assignments were not blinded, and clinicians could prescribe any form and schedule of ADT. Researchers reviewed men in both groups at a minimum of every 6 months, recording clinical symptoms and adverse events, with clinical examinations and imaging performed as indicated.
PSA levels were measured every 3 months for the first 2 years, followed by every 6 months through year 5 of the study. After 5 years, measurements occurred at the investigator’s discretion.
OS — measured from the time of randomization to death from any cause — served as the primary endpoint. Secondary measures included cause-specific survival, time to progression and global quality of life over the first 2 years.
Median follow-up was 5 years (interquartile range, 3.3-6.2 years).
Sixteen men (11%) assigned to immediate ADT died, compared with 30 men (20%) assigned to delayed ADT. Five-year OS was 91.2% (95% CI, 84.2-95.2) in the immediate therapy group compared with 86.4% (95% CI, 78.5-91.5) in the delayed therapy group (log-rank P = 0.47).
Analyses adjusted for study group, planned ADT schedule, PSA doubling time and treatment center showed the HR for OS with immediate vs. delayed ADT was 0.54 (95% CI, 0.27-1.06).
Forty men with PSA relapse died (immediate ADT, n = 14; delayed ADT, n = 26). In this cohort, estimated 5-year OS rates were 84.3% (95% CI, 73.9-90.8) for immediate ADT and 78.2% (95% CI, 67.2-85.8) for delayed ADT.
Six men with noncurable prostate cancer died (immediate ADT, n = 2; delayed ADT, n = 4). The researchers could not analyze OS in this subgroup due to the small number of participants.
Eighteen men (6%) died of prostate cancer (immediate ADT, n = 6; delayed ADT, n = 12). Ten men assigned immediate ADT and 18 men assigned delayed ADT died of other causes, including cardiac causes (immediate, n = 5; delayed, n = 4), other causes (immediate, n = 4; delayed, n = 9) and second malignancies (immediate, n = 1; delayed, n = 5).
Men assigned to immediate ADT had significantly longer times to local or distant progression. Eighteen men in the immediate therapy group experienced local progression, compared with 30 men assigned delayed therapy (HR = 0.51; 95% CI, 0.34-0.76).
Twenty-seven men assigned immediate therapy and 30 men assigned delayed therapy experienced distant progression.
Over 90% of participants completed quality-of-life questionnaires at each interval. Differences in global quality of life and overall scores decreased for both groups between baseline and the 2-year interval (P = .02).
“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,” Duchesne and colleagues wrote. “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.”
Several limitations might have affected the outcomes of this randomized trial, Peter R. Carroll, MD, MPH, professor and chair of urology at University of California, San Francisco’s Helen Diller Comprehensive Cancer Center, and Michael S. Leapman, MD, clinical urology fellow at University of California, San Francisco, wrote in an accompanying editorial.
“The men in Duchesne and colleagues trial were given ADT alone,” Carroll and Leapman wrote. “Addition of other drugs might better improve OS. The STAMPEDE trial showed an advantage in OS with the addition of docetaxel to ADT in patients with newly diagnosed metastatic disease. Men with high-risk nonmetastatic disease (ie, probably a similar population to the one in Duchesne and colleagues’ trial) had an improved RFS, but too few deaths occurred to show a survival benefit.” – by Cameron Kelsall
Disclosure: Duchesne reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Carroll reports grants and/or personal fees from Genomic Health, Medivation, Myriad Genetics and Takeda Pharmaceuticals outside of the submitted work. Leapman reports no relevant financial disclosures.
Perspective
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Alexander Kutikov, MD, FACS
Although immediate androgen deprivation therapy showed a modest improvement in this trial (5-year OS benefit of 86.4% vs. 91.2%), the impressive lack of a large difference in decreases to quality-of-life metrics makes these findings compelling and clinically actionable. ADT was associated with a statistically significant decrease in quality of life, but the difference in the quantifiable measures was extremely muted. Indeed, these data provide clinicians a seminal framework on which to base clinical decisions regarding ADT at the time of recurrence following local therapy.
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