Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European uroncological group

Background: Few randomised studieshave compared antiandrogen intermittent hormonal therapy (IHT) with continuousmaximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa).

Objective: To determine whetheroverall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS oncontinuous MAB.

Design, setting, and participants:This phase 3 randomised trial compared IHT and continuous MAB in patients withlocally advanced or metastatic PCa.

Intervention: During induction,patients received CPA 200 mg/d for 2 wk and then monthly depot injections of aluteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogueplus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stoppedtreatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml orthey were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRHanalogue).

Outcome measurements and statistical analysis: Primary outcome measurement was OS. Secondary outcomesincluded cause-specific survival, time to subjective or objective progression,and quality of life. Time off therapy in the intermittent arm was recorded.

Results and limitations: Werecruited 1045 patients, of which 918 responded to induction therapy and wererandomised (462 to IHT and 456 to continuous MAB). OS was similar betweengroups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]:0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for aninteraction between PSA and treatment (p=0.05), favouring IHT over continuoustherapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treatedwith IHT reported better sexual function. Among the 462 patients on IHT, 50%and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively,after randomisation. The main limitation is that the length of time for thetrial to mature means that other therapies are now available. A secondlimitation is that T3 patients may now profit from watchful waiting instead ofandrogen-deprivation therapy.

Conclusions: Noninferiority of IHTin terms of survival and its association with better sexual activity thancontinuous therapy suggest that IHT should be considered for use in routineclinical practice.