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

Calais da Silva, Fernando and Calais da Silva, Fernando Manuel and Gonçalves, Frederico and Santos, Américo and Kliment, Jan and Whelan, Peter and Oliver, Tim and Antoniou, Nicos and Pastidis, Spiro and Marques Queimadelos, Anton and Robertson, Chris (2014) 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. European Urology, 66 (2). pp. 232-239. ISSN 0302-2838

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Abstract

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.