Intermittent Androgen Deprivation in Prostate Cancer: Are We Ready to Quit?

In 1990, Bruchovsky et al reported in vivo experiments in the androgen-dependent Shionogi mammary carcinoma and the LNCaP hormone-sensitive prostate cancer models showing that the proportion of residual androgen-independent stem cells that survive androgen withdrawal was significantly reduced by reexposure to androgens. The authors suggested that the pluripotent residual cells adapt to the androgen-depleted environment and begin an androgen-independent growth, which can be delayed/reverted by re-exposure to androgens. Although at first one would predict that a clinical test of the intermittent androgen deprivation (IAD) hypothesis was relatively straightforward, 25 years later we still have no definitive evidence that this approach is a useful option for patients with prostate cancer who require androgen deprivation treatment. The increasingly recognized inherent challenges of capturing clinical outcomes in prostate cancer, conclusions not supported by observations of individual studies, and the emergence of new concepts in androgen receptor (AR) biology may suggest that this approach should be demoted to a lower priority in the research portfolio for this disease. In the article that accompanies this editorial, Hussain et al examine seven published randomized phase III trials comparing IAD with continuous androgen deprivation (CAD) for the treatment of prostate cancer. Hussain et al conclude that none of the trials demonstrated a superiority of IAD in terms of overall survival (OS), and that studies claiming equivalence and noninferiority presented serious flaws in study design and statistical analysis. In this editorial, we evaluate the current status of IAD in the context of current clinical and laboratory knowledge. For the purpose of this discussion, we adapted the tables of Hussain et al to emphasize various factors that we perceive as important to adequately evaluate the evidence (Table 1). Based on the initial preclinical data, it can be argued that the primary hypothesis to be tested was whether IAD would delay the emergence of clinically evident androgen independence and consequently delay progression-free survival (PFS). Although testing both PFS and OS together, in our opinion, is important for evaluating the clinical benefit of IAD versus CAD, the statistical implications of trials designed to test both PFS and OS are daunting. A lack of general consensus on a uniform definition of disease progression in the population with metastatic disease and the long post-progression survival, especially in patients with nonmetastatic disease, poses major challenges. The risk of death may change substantially after disease progression, possibly because of factors other than the treatment tested, and consequently, the impact on OS can be diluted, resulting in loss of statistical significance. As pointed out by Hussain et al, the outcome assumptions made for both PFS and OS to calculate sample sizes in all IAD studies were, to a great extent, conjectural. In fact, the outcome predictions in all seven trials were uniformly underestimated. Adequate capture of post-progression management patterns and outcomes, comorbidities, quality-of-life factors, and cause of death can affect the interpretation and analyses of survival outcomes. Table 1 illustrates the broad eligibility criteria, variable and somewhat elusive androgen deprivation therapy (ADT) and protocol management approaches, unspecified post-progression management, and unreferenced outcomes assumptions in the seven phase III trials. In three trials, SEUG 9401, 9901, and FinnProstate VII, the steroidal antiandrogen cyproterone acetate was combined with medical castration for prevention of flare, combined with androgen blockade strategy or as monotherapy. Although approved long ago for clinical use in Europe, cyproterone acetate has not been approved for the treatment of prostate cancer in the United States because of significant toxicity and lack of proven efficacy, and it is no longer used for the treatment of prostate cancer. To avoid the issue of patient heterogeneity based on stage of disease, we would like to focus our discussion on two trials, NCIC-CTG PR.7 and S9346. The NCIC-CTG PR.7 trial involved men with a rising prostate-specific antigen (PSA) after definitive radiotherapy and no evidence of metastatic disease. This is a population with a long and widely variable natural history, for whom the standard of care is not defined. The reported survival outcome in NCIC-CTG PR.7 trial was approximately 9 years in both IAD and CAD groups, and most patients died of causes other than prostate cancer. The question of how this information fits in the management of this patient population remains unanswered by NCIC-CTG PR.7 because it does not provide clarity regarding the role of ADT in the management of these patients. In the Johns Hopkins experience with deferred ADT (no ADT until metastases become evident clinically) in the population with nonmetastatic disease, the OS was about 11 years from PSA