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Intermittent androgen deprivation as effective as continuous therapy
Intermittent androgen deprivation therapy conferred similar survival outcomes and demonstrated similar adverse event profiles as continuous therapy, according to a study of patients with localized prostate cancer.
Prior studies have demonstrated the toxic effects of androgen deprivation, including sexual dysfunction, hot flashes, fatigue, anemia, and decreased bone density and muscle mass.
Researchers conducted the current randomized noninferiority trial to try to determine whether intermittent or continuous androgen deprivation therapy for PSA elevation could improve quality-of-life outcomes and delay hormone resistance.
The 1,386 eligible participants had a PSA level >3 ng/mL after more than 1 year of primary or salvage radiotherapy for localized disease.
Patients in the intermittent treatment arm (n=690) underwent androgen deprivation therapy in 8-month cycles. Non-treatment periods in this cohort were determined according to the PSA level.
OS served as the primary outcome measure. Secondary endpoints included quality of life, time to castration-resistant disease and duration of non-treatment intervals.
At the median follow-up point of 6.9 years, researchers observed no significant differences between the two groups in terms of adverse events.
Among patients in the intermittent therapy arm, 35% achieved full testosterone recovery, and testosterone recovery to the trial-entry threshold occurred in 79% of patients.
Intermittent treatment was associated with potential improvements in physical function, fatigue, urinary problems, hot flashes, libido and erectile function, results showed.
“Although intermittent androgen-deprivation therapy appears to provide an overall quality-of-life benefit, as compared with continuous androgen-deprivation therapy, the difference is not as profound as one might expect,” the researchers wrote. “Part of the explanation for this lies in the timing of the quality-of-life assessments, which were performed at regular intervals in both treatment groups without regard to the treatment phase (on or off treatment).”
The researchers reported 268 deaths in the intermittent arm compared with 256 in the continuous therapy arm.
The researchers reported a median OS of 8.8 years in the intermittent group and 9.1 years in the continuous group (HR for death=1.02; 95% CI, 0.86-1.21).
The estimated 7-year cumulative rate of disease-related death was 18% in the intermittent arm and 15% in the continuous arm (P=.24).
“This trial raises provocative questions,” the researchers wrote. “The nonsignificant increase in deaths from other causes among patients in the continuous-therapy group cannot be attributed to any specific type of toxic effect. Although the cost savings from the reduction in drug use in the intermittent-therapy group — approximately one third of that in the continuous-therapy group — may be partially offset by the closer follow-up required, this follow-up may have undefined health benefits.”
In an accompanying editorial, A. Oliver Sartor, MD, medical director of the Tulane Cancer Center, said the study is the most definitive to date that compares intermittent and continuous androgen-deprivation therapy in patients with nonmetastatic cancer.
However, questions still remain, Sartor said.
“What did we not learn from this trial? It is still unclear which men with rising PSA levels needed treatment,” Sartor wrote. “This is a heterogeneous patient group, and only a minority of men might be expected to have clinical consequences from their rise in PSA level. Given the slow progression of prostate cancer in many men, which of these asymptomatic patients actually benefitted from androgen-deprivation therapy? This important issue is not addressed.”
It also is unclear how many patients in the current study were unnecessarily exposed to the side effects and expense of androgen deprivation therapy, Crook said.
“In addition to knowing little about which men in this population would benefit from treatment as compared with no treatment, we know little regarding the best possible timing of androgen deprivation therapy for those clearly in need of treatment,” Crook wrote. “Does early androgen deprivation therapy in asymptomatic men with rising PSA levels provide more benefit than treatment in symptomatic men with metastases? This question bedevils our field, and we are no closer to an answer now than we were before.”
Perspective
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Although the standard of care for men with advanced prostate cancer — that is, men with serologic, radiographic or clinical progression after primary local therapy with either radical prostatectomy (RP) or radiation therapy (RT) — has not changed over the past 60 years, its timing and true impact on outcome remains controversial. Multiple randomized clinical trials using different statistical designs have tested the utility of androgen deprivation therapy at different stages of the disease. Due to the heterogeneity of these studies and the long natural history of prostate cancer, no consensus exists as to the best time to initiate testosterone suppression in men with advanced disease. The availability of PSA in routine clinical practice also has stalled our ability to rationalize the appropriate timing of treatment, as PSA has become the most common trigger for patients and practitioners to initiate treatment in patients with biochemical recurrence (BCR)-only disease. A better appreciation of the long-term complications of castration in men with prostate cancer has created a broader understanding of the potential implications of earlier treatment. Despite that, in the United States, rising PSA syndrome remains the most common setting in which practitioners initiate testosterone suppression therapy. Since medical castration was recognized as the standard of care in men with advance prostate cancer, continuous or indefinite ADT (CAB) has been the norm. Although contemporary, small phase 2 studies demonstrated the feasibility and safety of intermittent androgen blockade (IAB), it is only until recently that results of two large well-conducted randomized phase 3 studies comparing the efficacy and safety of IAB vs. CAB are available. As elegantly described by Crook and colleagues, the main rationale of the IAB approach comes from in vitro and animal studies that suggest that intermittent withdrawal of testosterone could delay the onset of castration-resistant disease. Translating this hypothesis to men with prostate cancer would imply their ability to remain testosterone dependent for longer periods of time, leading to a greater treatment benefit while enjoying better quality of life secondary to fewer adverse events from lack of testosterone. Although Dr. Crook’s study demonstrated that IAB was not inferior to CAB with respect to OS, the study failed to address the most fundamental question in this setting: What is the most appropriate timing to start ADT? In addition, the OS reported in this study could have been confounded by imbalances in subsequent therapy received at the onset of castration-resistant disease and other competing causes of mortality. It also does not address the OS of patients for whom ADT was started later (ie, at the time of symptomatic metastases). Other challenges of the study include the testosterone recovery data in men undergoing IAB. In their study, only 35% of men were able to recover testosterone to pretreatment levels. Similarly, there was no quality-of-life benefit favoring the IAB arm. When evaluating the impact of 3 months of testosterone suppression and the risk of developing metabolic syndrome and associated comorbidities, most patients undergoing IAB do not appear to escape this inherited risk. Often, patients initiating IAB receive an average of 6 to 12 months of ADT prior to therapy discontinuation. It also is important to recognize that, even at the time of ADT discontinuation, most men would either never recover their testosterone level or take a significant time to do so. Therefore, the question we should ask ourselves is not how to give ADT (ie, IAB vs. CAB with single gonadotropin-releasing hormone or in combination with antiandrogen), but rather when to give it and to whom, as not all patients are likely to derive the same benefit from early testosterone suppression.