Intermittent ADT failed to improve survival in metastatic prostate cancer

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

  • April 30, 2013

Intermittent androgen deprivation therapy failed to improve survival rates or quality of life compared with continuous therapy in patients with metastatic hormone-sensitive prostate cancer, according to study results.

Data from an androgen-dependent tumor model indicated that if androgens were replaced before progression of the disease, the remaining stem cells could generate an androgen-dependent tumor that would be vulnerable to hormonal manipulation.

Although androgen-sensitive models have suggested that intermittent androgen deprivation is inferior to castration in preventing tumor growth, clinical trials involving androgen-dependent models indicated that intermittent androgen deprivation resulted in reinduction of apoptosis, nearly tripling the time to castration resistance.

To assess whether intermittent androgen deprivation is noninferior to continuous androgen deprivation regarding prostate cancer survival, Maha Hussain, MD, FACP, professor of medicine and urology at the University of Michigan Comprehensive Cancer Center and a HemOnc Today Editorial Board member, and colleagues randomly assigned 1,533 patients with metastatic hormone-sensitive prostate cancer to continuous androgen deprivation (n=765) or intermittent androgen deprivation (n=770).

The study cohort included patients with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a PSA level of 5 ng/mL or higher. Patients received a luteinizing hormone-releasing hormone analogue and an anti-androgen agent for 7 months.

In addition, the researchers randomly assigned patients in whom the PSA level fell to 4 ng/mL or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status and extent of disease.

Study results showed median survival was 5.8 years in the continuous therapy group and 5.1 years in the intermittent-therapy group (HR for mortality with intermittent therapy, 1.10; 90% CI, 0.99-1.23). This translates to a 7-month difference in median survival.

“While we could not conclude that intermittent therapy is statistically significantly inferior to continuous therapy, a 7-month difference in median survival and survival trends that favored continuous therapy in all subgroups is clinically relevant and important,” Hussain told HemOnc Today. “This should also be viewed in the context of lack of scientific evidence from other clinical trials of ‘true equivalence’ between these treatment approaches.”

The effect of intermittent therapy on quality of life was modest, Hussain said. The researchers found that intermittent therapy initially was associated with improved erectile function (P<.001) and mental health (P=.003), but those differences leveled off after a few months and were not sustained.

“Based on the results of this trial, continuous androgen deprivation remains the standard based on optimal survival outcomes,” Hussain said. “Patients interested in intermittent therapy should be counseled regarding the potential negative impact on survival.”

Maha Hussain, MD, FACP, can be reached at University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109; email: mahahuss@umich.edu.

Perspective

Robert Dreicer

  • Long before prospective trial data was available, many clinicians embraced the concept of intermittent androgen deprivation therapy (ADT). It was theoretically attractive (ie, perhaps we could delay the development of castration-resistant disease, it provided a means to improve quality of life and appeared to be cost effective).

    Data from a Canadian randomized trial of intermittent ADT in men with PSA-only disease following radiotherapy provided evidence that intermittent therapy was “noninferior” to continuous ADT in terms of OS. Interestingly this study did not address the important question of whether early ADT should be used at all, just that if you did, it was reasonable to do so intermittently.

    In the current study of patients with metastatic prostate cancer, the authors note that the confidence interval for survival exceeded the upper boundary for noninferiority, meaning that for men managed with intermittent therapy, a 20% greater risk of death (ie, significant inferiority) could not be ruled out, as too few events had occurred.

    One of the take-home messages for me from this large, well done study is that continuous ADT for most patients remains the standard of care and, in those cases in which intermittent therapy is considered, the results of this study should be carefully reviewed with the patient prior to a final management decision.

    • Robert Dreicer, MD, FACP, FASCO
    • Department chair, Solid Tumor Oncology
      Cleveland Clinic Taussig Cancer Institute
  • Disclosures: Dreicer reports no relevant financial disclosures.
Perspective

Derek Raghavan

  • This is an extremely challenging paper to read in its final, published form. The New England Journal of Medicine set a particularly high bar for this paper, and changed it substantially from first submission to published version. The area that I personally find most difficult is the statistical section with complex statistical constructs of “non-inferiority,” etc.

    This was a well-powered study that was designed to inform clinicians whether continuous hormonal suppression should be used as the only safe option for first-line castration in advanced prostate cancer. This was set against a background that patients seem to benefit from their “castration holiday” when intermittent hormone suppression is used — due to fewer side effects — and a preclinical construct that intermittent cessation of hormones might actually give a benefit in allowing androgen responsiveness to return and be maintained. Although this study did not show a vast difference in outcome, there was a trend in favor of continuous suppression.

    In the patient for whom survival is the absolute “driver” (ie, the one who wants the absolutely best chance of survival), continuous castration offers the best approach, provided that significant toxic events don’t supervene. However, in the patient for whom long survival is desirable but where quality of life is of equal importance (eg, more time without side effects of castration provides better quality of life), intermittent castration is a reasonable option.

    I was surprised that the final analysis showed that, with the passage of time, the side effects of intermittent castration increased to approximate those of continuous castration, so that there wasn’t significant difference. However, for those patients who were randomly allocated to the intermittent arm, and who sustained long remissions without re-starting castration, the quality of life was clearly improved.

    • Derek Raghavan, MD, PhD, FACP, FRACP
    • HemOnc Today Editorial Board member
  • Disclosures: Raghavan was a co-investigator on this study.