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

Fernando Calais da Silva, Fernando Manuel Calais da Silva, Frederico Gonçalves, Américo Santos, Jan Kliment, Peter Whelan, Tim Oliver, Nicos Antoniou, Spiro Pastidis, Anton Marques Queimadelos, Chris Robertson

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

LanguageEnglish
Pages232-239
Number of pages8
JournalEuropean Urology
Volume66
Issue number2
Early online date4 Apr 2013
DOIs
Publication statusPublished - Aug 2014

Fingerprint

Androgens
Prostatic Neoplasms
Therapeutics
Hormones
Watchful Waiting
Cyproterone Acetate
Androgen Antagonists
Survival
Prostate-Specific Antigen
Random Allocation
Gonadotropin-Releasing Hormone
Sexual Behavior
Injections

Keywords

  • maximal androgen blockade
  • intermittent antiandrogen therapy
  • prostate cancer
  • cyproterone acetate
  • prostate specific antigen
  • triptorelin

Cite this

Calais da Silva, Fernando ; Calais da Silva, Fernando Manuel ; Gonçalves, Frederico ; Santos, Américo ; Kliment, Jan ; Whelan, Peter ; Oliver, Tim ; Antoniou, Nicos ; Pastidis, Spiro ; Marques Queimadelos, Anton ; Robertson, Chris. / 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. In: European Urology. 2014 ; Vol. 66, No. 2. pp. 232-239.
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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.",
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Calais da Silva, F, Calais da Silva, FM, Gonçalves, F, Santos, A, Kliment, J, Whelan, P, Oliver, T, Antoniou, N, Pastidis, S, Marques Queimadelos, A & Robertson, C 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, vol. 66, no. 2, pp. 232-239. https://doi.org/10.1016/j.eururo.2013.03.055

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; Calais da Silva, Fernando Manuel; Gonçalves, Frederico; Santos, Américo; Kliment, Jan; Whelan, Peter; Oliver, Tim; Antoniou, Nicos; Pastidis, Spiro; Marques Queimadelos, Anton; Robertson, Chris.

In: European Urology, Vol. 66, No. 2, 08.2014, p. 232-239.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade

T2 - European Urology

AU - Calais da Silva, Fernando

AU - Calais da Silva, Fernando Manuel

AU - Gonçalves, Frederico

AU - Santos, Américo

AU - Kliment, Jan

AU - Whelan, Peter

AU - Oliver, Tim

AU - Antoniou, Nicos

AU - Pastidis, Spiro

AU - Marques Queimadelos, Anton

AU - Robertson, Chris

PY - 2014/8

Y1 - 2014/8

N2 - 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.

AB - 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.

KW - maximal androgen blockade

KW - intermittent antiandrogen therapy

KW - prostate cancer

KW - cyproterone acetate

KW - prostate specific antigen

KW - triptorelin

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DO - 10.1016/j.eururo.2013.03.055

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SP - 232

EP - 239

JO - European Urology

JF - European Urology

SN - 0302-2838

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