Androgen Deprivation Therapy in Advanced Prostate Cancer: Is Intermittent Therapy the New Standard of Care?

Abstract

Purpose: Intermittent androgen deprivation is increasingly used as an alternative to continuous life-long androgen deprivation therapy for men with advanced or recurrent prostate cancer. Recent Findings: Two recent phase III trials have clarified the benefits of intermittent therapy. The Canadian-led pr.7 trial in men with nonmetastatic disease and prostate-specific antigen recurrence after definitive local therapy showed that intermittent therapy resulted in survival equivalent to that with continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experienced improved bone health, fewer metabolic and hematologic disturbances, fewer hot flashes, and improved sexual function. In men with metastatic disease, the data are less clear. The long-awaited results of the Southwest Oncology Group 9346 trial, comparing intermittent with continuous therapy in metastatic disease, showed no difference in overall survival. Post hoc stratification analysis showed a worse outcome in patients with “minimal” metastatic disease, and no difference in those with widespread bone metastases. The significance of that observation is in dispute. The present review also addresses practical issues in the use of intermittent therapy, including patient selection, follow-up, and therapy cycling. Summary: The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care in most patients with nonmetastatic prostate cancer requiring hormonal therapy and in selected patients with metastatic disease. Key Points: (1) Level I evidence supports the oncologic equivalence of intermittent compared with continuous androgen blockade in men with biochemical failure. (2) Compared with continuous androgen deprivation, intermittent therapy demonstrates improved quality of life and fewer side effects. (3) Patient selection for intermittent therapy is important to maintain good oncologic results. (4) Monitoring of prostate-specific androgen response and duration of off-treatment intervals allow for stratification of patients by risk of progression.

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

“…In fact, survival in two of the M1 trials (S9346 and TAP22) was worse for the IAD arm compared with the CAD arm. 7,10 Interestingly, many of the recent reviews concluded that IAD is as effective as CAD in PC [2][3][4][5][6]17 ; however, these reviews often overlooked important issues, such as NIM selection including clinically meaningful differences in survival, follow-up time too short to observe disease-specific end points, suboptimal design of mixed patient populations, and small underpowered trials.…”

Mathematical Models of Androgen Resistance in Prostate Cancer Patients under Intermittent Androgen Suppression Therapy

“…The development of CRPC can take from a few months to more than ten years [3,6], after which there is a very limited number of effective treatments and patients suffer high mortality [7]. ADT is expensive and its side effects include sexual dysfunction, hot flashes, and fatigue [8]. Based on some preclinical studies, intermittent androgen suppression (IAS) is suggested as a sensible alternative to ADT [9].…”

“…Based on some preclinical studies, intermittent androgen suppression (IAS) is suggested as a sensible alternative to ADT [9]. During off-treatment periods, patients enjoy a "vacation" from the severe side effects of ADT [8], and studies have suggested that IAS may not negatively affect the time to resistance progression or survival in comparison to ADT [10]. Consequently, IAS is selected by some patients to improve the quality of life and also hopefully to delay the progression to CRPC [4].…”

Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer

“…3), and response to the next cycle of ADT. 35 The fact that low levels of testosterone are beneficial during ADT treatment does not imply that these low levels must be continuously sustained to achieve the benefit.…”