Landmark ADT Study Now Published in NEJM

Nick Mulcahy

April 03, 2013

Receiving androgen-deprivation therapy (ADT) on an intermittent basis does not appear to be a wise choice for men with metastatic hormone-sensitive prostate cancer, according to a landmark trial published in the April 4 issue of the New England Journal of Medicine.

After a median follow-up of about 10 years, the study authors found that 765 men treated with continuous therapy lived longer than 770 men treated intermittently (average survival, 5.8 vs 5.1 years).

These outcomes translate to a 10% increase in the relative risk for death with the intermittent approach (hazard ratio, 1.10; 90% confidence interval, 0.99 - 1.23).

The result suggests that intermittent therapy may compromise survival.

"The result suggests that intermittent therapy may compromise survival. The lack of a significant difference between the groups does not imply similar survival," write the authors, led by Maha Hussain, MD, from the University of Michigan in Ann Arbor.

The trial does not rule out "significant inferiority" of intermittent therapy, which was 1 of the 2 primary goals of the trial, they note.

Dr. Hussain first presented results from the study — the Southwest Oncology Group (SWOG) 9346 trial — last year at the annual meeting of the American Society of Clinical Oncology (ASCO), as reported at the time by Medscape Medical News.

Quality of life, which was other primary end point of the study — and is a selling point for the on-again, off-again approach — was not dramatically better with intermittent therapy. Intermittent therapy was associated with better erectile function (P < .001) and mental health (P = .003) at month 3, but not thereafter.

At the ASCO meeting, Dr. Hussain said that the findings go against "conventional belief." She was referring to the fact that many clinicians and academics have believed, on the basis of previous research, that intermittent therapy could prolong disease response, or at least would not be detrimental in terms of survival.

The impetus for using intermittent ADT has also been to relieve men of the adverse effects of low testosterone, such as impotence and diminished well being, Dr. Hussain added.

The study results indicate that "there is a price to pay" for using ADT intermittently, Bruce J. Roth, MD, from the Washington University School of Medicine in St. Louis, Missouri, who was not involved with the study, said at the ASCO meeting.

Dr. Hussain believes that the study results provide clear guidance for clinicians. "If a patient is coming in with newly metastatic prostate cancer, hormone treatment continuously is the standard. If they wish to do intermittent treatment, they should be counseled that, based on these data, their outcome might be compromised," she said in a press statement.

The study results apply only to men who are treated in a manner similar to the study protocol, and not to various other androgen-deprivation regimens.

The study design called for all men to undergo a 7-month induction course of "combined" ADT (subcutaneous goserelin once a month and oral bicalutamide once daily for 8 courses).

Men whose prostate-specific antigen (PSA) levels decreased to 4 ng/mL or less after months 6 and 7 of induction treatment, and who had a stable or declining trend, were deemed hormone sensitive and randomly assigned to either intermittent or continuous ADT for the duration of the trial. Men on intermittent therapy had their treatment initially discontinued and were monitored with monthly PSA tests; ADT was restarted if values exceeded prespecified levels.

Other Trial Addressed at Length

Another major clinical trial — NCIC-CTG PR.7 — has compared intermittent with continuous ADT in men with prostate cancer, but they had localized disease with PSA progression after radiation treatment.

The results of that trial, reported at the 2011 Genitourinary Cancers Symposium, demonstrated that intermittent therapy was noninferior to continuous therapy with respect to overall survival (median, 8.8 vs 9.1 years).

These results in earlier-stage prostate cancer lent credibility to the idea that intermittent therapy would not compromise survival in men with metastatic disease.

Dr. Hussain and her coauthors address these "apparently contradictory results" in their study.

They suggest that "a plausible explanation" is that the NCIC-CTG PR.7 trial targeted a population with a lower disease burden; hence, the risk for cancer-related death was lower than in their study. In a population with a lower disease burden, a longer median follow-up than the reported 6.9 years might be required to observe enough deaths from cancer to counterbalance the deaths from other causes that are usually observed earlier in a population of older men, the authors write.

Also, only 41% of deaths in the NCIC-CTG PR.7 trial were related to prostate cancer, with a trend toward fewer prostate-cancer-related deaths in the continuous-therapy group than in the intermittent-therapy group (94 vs. 120).

Other phase 3 trials testing intermittent therapy have involved mixed populations (patients with locally advanced disease and those with metastatic disease) or were not adequately powered to assess survival, note Dr. Hussain and her coauthors.

In other words, this study is the most definitive word to date on intermittent therapy in metastatic disease.

This study was supported in part by the National Cancer Institute and AstraZeneca. Dr. Hussain and some of her coauthors report financial relationships with industry, including AstraZeneca, as detailed in the paper.

N Engl J Med. 2013;368:1314-1325. Abstract


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