1014
EUROPEAN UROLOGY 65 (2014) 1010–1015
arm. The basis of a randomized phase 3 trial is to oppose an experimental arm with the best valuable comparator. In the retrospective review by Moul et al., it was clearly suggested that except for a subset of patients with a high Gleason and rapid PSA doubling time, there was no benefit of immediate ADT on the time to metastatic progression [3]. In the recently updated European Organisation for Research and Treatment of Cancer 30891 trial, Studer et al. failed to demonstrate that immediate ADT significantly delays castration resistance or PCa mortality in patients with locally advanced disease, except in those men with aggressive disease [4]. IAD trials have been forged on the conventional wisdom that CAD was indeed a best valuable comparator, which is not appropriate. As academics, maybe we should shout louder that for most patients, CAD should be substituted not by IAD but by careful monitoring of the patient.
References [1] Huggins C, Stevens Jr RE, Hodges CV. The effect of castration on advanced carcinoma of the prostate gland. Arch Surg 1941;43:209. [2] Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24. [3] Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 2004;171:1141–7. [4] Studer UE, Whelan P, Wimpissinger F, et al. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2013.07.024 Bertrand Tombal Institut de Recherche Clinique, Service d’Urologie, Cliniques universitaires Saint Luc, Avenue Hippocrate 10, B-1200 Brussels, Belgium
Conflicts of interest: Bertrand Tombal has been or is an investigator
E-mail address: [email protected].
and/or a paid consultant for Astellas, Bayer, Medivation, Janssens, Ferring, and Ipsen.
http://dx.doi.org/10.1016/j.eururo.2013.12.041
Re: Pazopanib Versus Sunitinib in Metastatic Renal-cell Carcinoma Motzer RJ, Hutson TE, Cella D, et al.
4 wk after initial treatment, following the 4 wk on, 2 wk off regimen [2]. The discrepant timing in disease assessments may have contributed to a premature determination of disease progression under the Response Evaluation Criteria in Solid Tumors criteria, when the tumor may have still been responsive to sunitinib. Indeed, patients randomized to receive sunitinib in the COMPARZ study had poorer median PFS (9.5 vs 11 mo) and poorer response rates (25% vs 47%) than in the pivotal sunitinib trial [2]. This observation also likely contributed to less favorable health-related quality-of-life (HRQOL) measurements. Specifically, toxicity is known to peak after a 4-wk treatment with sunitinib, in which an improvement in adverse events is seen during the 2 wk off period. The appropriateness of the timing of safety and tolerability assessments may also be questionable, given the intermittent administration of sunitinib relative to the continuous dosing of pazopanib. Finally, the validity of the noninferiority trial should raise concern, given that results of the intention-to-treat analysis (upper bound 95% CI, 1.22) differed from the per-protocol analysis (upper bound 95% CI, 1.255); the latter did not even meet noninferiority criteria. This specification is especially important when examining noninferiority trials, which are designed to ascertain whether a novel treatment (ie, pazopanib) is neither better nor worse than the current standard (ie, sunitinib). In superiority trials, intention-to-treat analysis yields an unbiased comparison compared with perprotocol analysis, since intention-to-treat analysis analyses patients in the groups in which they were assigned, irrespective of patient adherence. In noninferiority trials, however, both intention-to-treat and per-protocol analyses are equally relevant; consistent outcomes strengthen noninferiority results, while inconsistent outcomes weaken them. In conclusion, we are unwilling to accept that contemporary MRCC patients should accept an efficacy trade-off of up to 25% for better tolerability and HRQOL, given that the discontinuation rate due to adverse events was lower for
N Engl J Med 2013;369:722–31 Experts’ summary: To date, seven US Food and Drug Administration–approved targeted therapy options are available for patients with metastatic renal cell carcinoma (MRCC) [1,2]. Therefore, direct headto-head comparisons are necessary to substantiate the choice of treatment. Whereas sunitinib has traditionally been considered the first-line standard of care, indirect comparisons between pazopanib and sunitinib—both considered an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor and platelet-derived growth factor receptor—have suggested similar progression-free survival (PFS) benefits. Recently, a randomized noninferiority phase 3 trial was published comparing pazopanib and sunitinib among 1110 exclusively treatment-naive MRCC patients. The COMPARZ trial showed no statistically significant difference with respect to PFS between pazopanib and sunitinib: median PFS 8.4 compared with 9.5 mo, respectively (hazard ratio: 1.05; 95% confidence interval [CI], 0.90–1.22), thereby satisfying the predetermined noninferiority threshold margin (upper bound of the 95% CI,
EUROPEAN UROLOGY 65 (2014) 1010–1015
arm. The basis of a randomized phase 3 trial is to oppose an experimental arm with the best valuable comparator. In the retrospective review by Moul et al., it was clearly suggested that except for a subset of patients with a high Gleason and rapid PSA doubling time, there was no benefit of immediate ADT on the time to metastatic progression [3]. In the recently updated European Organisation for Research and Treatment of Cancer 30891 trial, Studer et al. failed to demonstrate that immediate ADT significantly delays castration resistance or PCa mortality in patients with locally advanced disease, except in those men with aggressive disease [4]. IAD trials have been forged on the conventional wisdom that CAD was indeed a best valuable comparator, which is not appropriate. As academics, maybe we should shout louder that for most patients, CAD should be substituted not by IAD but by careful monitoring of the patient.
References [1] Huggins C, Stevens Jr RE, Hodges CV. The effect of castration on advanced carcinoma of the prostate gland. Arch Surg 1941;43:209. [2] Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24. [3] Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 2004;171:1141–7. [4] Studer UE, Whelan P, Wimpissinger F, et al. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2013.07.024 Bertrand Tombal Institut de Recherche Clinique, Service d’Urologie, Cliniques universitaires Saint Luc, Avenue Hippocrate 10, B-1200 Brussels, Belgium
Conflicts of interest: Bertrand Tombal has been or is an investigator
E-mail address: [email protected].
and/or a paid consultant for Astellas, Bayer, Medivation, Janssens, Ferring, and Ipsen.
http://dx.doi.org/10.1016/j.eururo.2013.12.041
Re: Pazopanib Versus Sunitinib in Metastatic Renal-cell Carcinoma Motzer RJ, Hutson TE, Cella D, et al.
4 wk after initial treatment, following the 4 wk on, 2 wk off regimen [2]. The discrepant timing in disease assessments may have contributed to a premature determination of disease progression under the Response Evaluation Criteria in Solid Tumors criteria, when the tumor may have still been responsive to sunitinib. Indeed, patients randomized to receive sunitinib in the COMPARZ study had poorer median PFS (9.5 vs 11 mo) and poorer response rates (25% vs 47%) than in the pivotal sunitinib trial [2]. This observation also likely contributed to less favorable health-related quality-of-life (HRQOL) measurements. Specifically, toxicity is known to peak after a 4-wk treatment with sunitinib, in which an improvement in adverse events is seen during the 2 wk off period. The appropriateness of the timing of safety and tolerability assessments may also be questionable, given the intermittent administration of sunitinib relative to the continuous dosing of pazopanib. Finally, the validity of the noninferiority trial should raise concern, given that results of the intention-to-treat analysis (upper bound 95% CI, 1.22) differed from the per-protocol analysis (upper bound 95% CI, 1.255); the latter did not even meet noninferiority criteria. This specification is especially important when examining noninferiority trials, which are designed to ascertain whether a novel treatment (ie, pazopanib) is neither better nor worse than the current standard (ie, sunitinib). In superiority trials, intention-to-treat analysis yields an unbiased comparison compared with perprotocol analysis, since intention-to-treat analysis analyses patients in the groups in which they were assigned, irrespective of patient adherence. In noninferiority trials, however, both intention-to-treat and per-protocol analyses are equally relevant; consistent outcomes strengthen noninferiority results, while inconsistent outcomes weaken them. In conclusion, we are unwilling to accept that contemporary MRCC patients should accept an efficacy trade-off of up to 25% for better tolerability and HRQOL, given that the discontinuation rate due to adverse events was lower for
N Engl J Med 2013;369:722–31 Experts’ summary: To date, seven US Food and Drug Administration–approved targeted therapy options are available for patients with metastatic renal cell carcinoma (MRCC) [1,2]. Therefore, direct headto-head comparisons are necessary to substantiate the choice of treatment. Whereas sunitinib has traditionally been considered the first-line standard of care, indirect comparisons between pazopanib and sunitinib—both considered an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor and platelet-derived growth factor receptor—have suggested similar progression-free survival (PFS) benefits. Recently, a randomized noninferiority phase 3 trial was published comparing pazopanib and sunitinib among 1110 exclusively treatment-naive MRCC patients. The COMPARZ trial showed no statistically significant difference with respect to PFS between pazopanib and sunitinib: median PFS 8.4 compared with 9.5 mo, respectively (hazard ratio: 1.05; 95% confidence interval [CI], 0.90–1.22), thereby satisfying the predetermined noninferiority threshold margin (upper bound of the 95% CI,
