Intermittent androgen blockade should be regarded as standard therapy in prostate cancer

Bostjan Seruga and Ian F Tannock*  About the authors

Androgen deprivation (AD) therapy for prostate cancer is being used in an increasingly wide range of settings, such as advanced disease, loco-regional disease, as an adjunct to surgery or radiotherapy, and in patients with rising prostate-specific antigen (PSA) levels after local therapy. More than 80% of men with advanced prostate cancer will respond to AD therapy, experiencing improvement in disease-related symptoms and a marked reduction in level of serum PSA. The standard of care for advanced prostate cancer has been continuous AD therapy, usually combined with an agonist of gonadotropin releasing hormone (GnRH) such as goserelin acetate or leuprolide. A peripheral anti-androgen is given briefly before and during initiation of such treatment to prevent disease flare. AD therapy is associated with several side-effects that impair the patient's quality of life, including sexual dysfunction, osteoporosis, hot flashes, fatigue, gynecomastia, anemia and, in some patients, depression and cognitive dysfunction.¹ The metabolic syndrome—a known risk factor for cardiovascular disease that is characterized by reduced glucose tolerance, increased body fat and altered lipid profile—is also associated with AD therapy.² An observational study of a population-based cohort of 73,196 men with loco-regional prostate cancer showed that patients treated with continuous AD therapy had a significantly increased risk for cardiovascular morbidity and mortality.³

In contrast to normal prostatic epithelial cells, which are not able to regenerate and grow in an androgen-deprived state, prostate cancer cells almost always manage to acquire an androgen-independent phenotype. Most patients receiving continuous AD therapy for advanced disease develop androgen resistance and disease progression within 2–3 years of starting treatment.

Several years ago, investigators working in Vancouver on animal models of prostate cancer reported a series of experiments that showed that in comparison with continuous AD therapy, intermittent AD substantially prolonged the time to development of androgen-independent disease.^{4, 5} These preclinical results provided support for clinical trials of intermittent AD treatment in men with prostate cancer, with the aim of minimizing the side-effects of AD therapy while maximizing the clinical benefits of this treatment and the quality of life of the patient. Intermittent AD therapy consists of monitoring serum PSA levels and stopping treatment when a low PSA level is reached. The PSA level is allowed to rise until it reaches an empirically determined level, at which point AD therapy is restarted. Cycles of intermittent AD are then continued until clinical or PSA progression is evident. The concept assumes recovery of testosterone levels during the periods in which the patient is not receiving treatment.

Investigators have now reported results from four randomized controlled phase III studies that compared continuous and intermittent AD therapy in more than 1,000 men who had various treatment histories and were at different stages of disease progression. A table showing the randomized trials of intermittent and continuous AD therapy is provided in Supplementary Table 1 online. Only one of the studies has been published;⁶ the results of the other three have been presented at major international meetings with reports available in abstract form.^{7, 8, 9} Despite being unpublished, these studies consistently support the noninferiority of intermittent AD to continuous AD with regards to time-to-disease progression and survival. Furthermore, the studies suggest a trend towards improved quality of life with intermittent AD.

de Leval et al.⁶ reported a small clinical trial that randomized 68 patients with advanced prostate cancer to intermittent or continuous AD therapy with goserelin acetate and flutamide. After a median follow-up of 30.8 months, 3-year androgen-independent progression rate was significantly lower in the intermittent arm than in the continuous arm (7% vs 38.9%, P = 0.0052). Patients receiving intermittent therapy were off treatment 59% of the time.

The European phase III study EC 507 (RELAPSE) compared intermittent and continu-ous AD with leuprolide acetate (and flare prophylaxis with cyproterone acetate) in 167 patients with biochemical relapse after radical prostatectomy.⁷ The results showed no significant difference in time to androgen-independent progression in the two treatment groups. Men receiving intermittent AD had less hot flashes and fluid retention than men receiving continuous AD.

A multicentric phase III German study (AUO AP 17/95) compared intermittent and continuous AD with goserelin acetate and bicalutamide in 335 patients with loco-regional or distant metastases.⁸ After a median follow-up of 50.5 months, time to progression and survival were comparable in the two treatment arms. Most patients receiving intermittent AD spent more than 50% of the study period off therapy and had better general well-being and sexual function.

A phase III study conducted by the South European Urological Group (SEUG) is comparing intermittent and continuous AD with triptoreline pamoate and cyproterone acetate; a preliminary report of survival in 626 patients with locally advanced and advanced prostate cancer is currently available.⁹ After a median follow-up of 51 months, progression-free and overall survival were comparable in the two arms, with better quality of life, improved sexual activity and decreased hot flushes reported in the intermittent arm. Patients with an initial good PSA response had spent a median of 82% of the study period off therapy in the intermittent arm.

Results are expected from two highly powered large phase III North American trials in the near future. NCIC PR.7/SWOG JPR7 and NCIC PR.8/SWOG 9346 are comparing intermittent and continuous AD therapy in patients with biochemical relapse after radiotherapy, and in patients with advanced disease, respectively. The primary end points in both studies are quality of life and overall survival.

Even though most studies have thus far been reported only in abstract form, the consistent findings of (at least) noninferiority of intermittent AD in terms of time to progression and overall survival with decreased side-effects and the supporting preclinical data indicate that intermittent AD should now replace continuous AD as the standard of care in patients with prostate cancer.

Some important questions still need to be addressed. All but one of the randomized clinical trials evaluating intermittent AD therapy is using a combination of a GnRH analog and an anti-androgen in both arms (i.e. maximal androgen blockade [MAB]). In a patient-based meta-analysis of 27 trials comprising more than 8,000 patients, however, MAB did not confer a significant survival benefit over monotherapy with GnRH agonists or orchidectomy in advanced or locally advanced prostate cancer.¹⁰ On the basis of survival data, the increased toxicity and cost associated with continuous MAB cannot be considered standard primary hormonal treatment in prostate cancer. Future clinical trials comparing continuous and intermittent AD should evaluate monotherapy with GnRH analogs with the use of an anti-androgen only briefly to prevent tumor flare. Information is also needed about the optimum use of intermittent AD in different settings of prostate cancer (e.g. biochemical relapse vs advanced disease, rapidly vs slowly progressing disease) and about optimum scheduling. At present we do not know the optimum duration of initial AD treatment, or the optimum serum PSA levels at which treatment should be stopped or resumed. Future clinical trials should evaluate these components of intermittent therapy.

In summary, there are now compelling data to indicate that intermittent AD should be regarded as standard therapy in prostate cancer. Intermittent therapy is at least as effective as continuous AD, and is a safe and reasonable standard in settings of hormone-responsive prostate cancer studied in randomized controlled phase III trials. The main advantages of intermittent AD therapy are: first, the patient has a shorter duration on a potentially toxic therapy and better quality of life; and secondly, the costs of this treatment strategy are markedly lower than those of continuous AD. Future clinical trials should be designed to provide information about how to further optimize and refine intermittent hormonal treatment for men with prostate cancer.

Competing interests

The authors declared no competing interests.

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