Early ADT May Not Up OS in Prostate Cancer With PSA Relapse

Early initiation of continuous androgen-deprivation therapy (ADT) for prostate cancer patients who experience biochemical relapse may not meaningfully improve overall survival, according to new findings.

A retrospective analysis with data from two institutions found that metastasis-free survival and overall survival were quite long among those who delayed hormone therapy. Among patients who experienced biochemical recurrence and whose prostate-specific antigen (PSA) doubling time was <6 months, median metastasis-free survival was 144 months; for those whose PSA doubling time was <10 months, median metastasis-free survival was 192 months.

Median overall survival was 168 months and 204 months, respectively.

“These results are in line with the estimated survival times of men treated in contemporary trials of anti-androgens for nmCRPC [nonmetastatic castration- resistant prostate cancer],” observe the authors, who were led by Catherine Handy Marshall, MD, MPH, of Johns Hopkins University School of Medicine, Baltimore, Maryland.

“Prospective randomized data would provide the best evidence, but without that, we are left with retrospective data,” said Marshall. “But it should be a discussion between patients and providers about whether or not to start androgen-deprivation therapy, because not starting it right at time of biochemical recurrence is a reasonable choice too.”

The study was published online June 11 in The Journal of Urology.

Biochemical recurrence is defined as a rise in PSA to 0.2 ng/mL and a confirmatory value of ≥0.2 ng/mL following radical prostatectomy, or a rise of ≥2 ng/mL above the nadir PSA after radiotherapy. Not all men whose PSA level rises will develop metastases, and there is a lack of high-level evidence supporting the use of continuous ADT alone in the setting of PSA relapse, the authors note.

The team further described the men that they studied: “We sought to examine what the life expectancy is in a cohort of patients who developed biochemical recurrence but were not immediately treated with androgen deprivation therapy…and therefore could not develop nmCRPC.” Notably, patients in the study were considered to be at high risk because of the time frame of their relapse (≤10 months).

Early initiation of continuous ADT in men with prostate cancer who experience biochemical recurrence has led to a new paradigm, nmCRPC, the authors point out. The practice of initiating early ADT remains unsubstantiated by level I evidence. Reports on the natural history of patients with biochemical resistance indicate that these patients are heterogeneous in terms of natural progression of metastasis and survival.

Importantly, because these patients typically survive for many years and have virtually no symptoms until metastasis, factors regarding quality of life are crucial, inasmuch as ADT is associated with significant side effects and major costs.

Study Details

In this study, Marshall and colleagues examined the outcomes for men with biochemically recurrent prostate cancer for whom ADT was delayed until time of metastasis. The cohort included 806 patients from two medical centers who underwent radical prostatectomy for clinically localized prostate cancer and whose PSA doubling time was ≤10 months.

The primary endpoints were metastasis-free survival and overall survival from time of local treatment among men for whom ADT was delayed until time of metastasis.

The median age of the cohort was 61 years, most men were White (79%), and 38% had positive surgical margins; 17% had a Gleason score of ≤6, 54% had a Gleason score of 7, and 29% had a Gleason score of 8–10. The median time to PSA doubling was 5.6 months, and the median follow-up was 9 years.

In multivariable analysis, Black race was associated with a lower risk for metastasis compared to White race (hazard ratio [HR], 0.5). Time from radical prostatectomy to biochemical recurrence correlated with the risk of developing metastatic disease (HR, 0.8).

A PSA doubling time of <6 months was associated with a higher risk of developing metastatic disease in comparison with a doubling time of 6–10 months (HR, 3.2).

Older age, higher pathologic T stage, higher Gleason sum, and faster PSA doubling time were all associated with higher likelihood of death.

Still No Definitive Answers

In an accompanying editorial, David VanderWeele, MD, and Maha Hussain, MD, both from the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, note that the question of how best to manage biochemical recurrence remains controversial.

The current study contributes to this debate, and “these data provide context for patients with biochemical response and providers on whether to undergo ADT for years despite unproven benefit and quality of life impact,” they write. “New imaging may help or further add to the controversy, since biochemical response patients may have metastases on newer imaging.”

Until definitive data are available, they advise that these patients “be counselled regarding the lack of data to support ADT benefit in nonmetastatic biochemical recurrence.”

The study was partly supported by National Institutes of Health Cancer Center support grants. Marshall and the editorialists have disclosed no relevant financial relationships.

J Urol. 2021 Sep;206:623-629. Full text, Editorial

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