EURURO-5546; No. of Pages 3 EUROPEAN UROLOGY XXX (2014) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer Michael R. Harrison a,*, Andrew J. Armstrong a,b a
Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; b Department of Surgery, Duke Cancer Institute, Duke
University Medical Center, Durham, NC, USA
In this issue of European Urology, Azad et al. report on the real-world experience in Canada of men with metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen synthesis inhibitor abiraterone acetate (AA) with prednisone [1]. The investigators focused on men with poor functional status as determined by the Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, given that patients with poor functional status were underrepresented in the phase 3 trials of AA and are actually more likely to receive this agent in practice compared with taxane-based chemotherapy for multiple reasons. Functional status can be determined by a number of host and tumor-specific factors, ranging from comorbidities and age to prior therapies, neuropathy, anemia, cancerrelated fatigue, or pain. The authors analyzed a number of prognostic factors, including prior castration sensitivity, the pattern of metastatic spread, and biomarkers such as lactate dehydrogenase (LDH), alkaline phosphatase, hemoglobin, and prostate-specific antigen (PSA); in the end, PS was clearly an important and independent factor in determining response and survival with AA in this population. What does this paper do to advance our knowledge and treatment decision making? The authors are to be commended for conducting this study in a population of mCRPC patients for whom there is currently a paucity of data: patients with ECOG PS 2. As drugs are approved, they are commonly used in broader populations than those included in clinical trials. AA, in particular, may be used in real-world patients with poorer PS preferentially over chemotherapies because of AA’s relatively tolerable adverse effect profile. As the authors
point out, only 10% of patients in the COU-AA-301 (after docetaxel) study had PS 2, and by design, none of the patients in the COU-AA-302 (before docetaxel) study had PS 2. In contrast, approximately 40% of this Canadian cohort had PS 2, and 38% of this group was docetaxel-naive. The reasons for this large difference between the clinical trial and real-world populations are not entirely clear but likely reflect decisions made in the pivotal clinical trial designs to enrich for patients most likely to benefit from and least likely to be harmed by AA. Both the docetaxelpretreated and docetaxel-naive groups had inferior outcomes in patients with PS 2 compared with PS 0–1. PS remained a significant prognostic factor even with inclusion of post–abiraterone systemic therapy, which was more frequent in the PS 0–1 group, in the multivariate model. These results are not entirely surprising, as baseline PS is known to be prognostic in multiple settings in mCRPC, both before chemotherapy [2–4] and after chemotherapy [5]. PS 2 was identified as a factor associated with a poor prognosis in the COU-AA-301 trial [6]. Deterioration in PS reflects a range of host factors including comorbidity, but it also is reflective of a higher disease burden and more aggressive and disseminated disease; this more aggressive tumor phenotype may be more likely to have redundant pathways and develop resistance more quickly to systemic therapy. Unfortunately, one of the most interesting clinical questions—whether patients with PS 2 derive a survival benefit from AA—cannot be answered by this study. Despite the poor outcomes for patients with PS 2, there was no comparator arm; thus, the conclusion that these patients derive little or no benefit from AA cannot be inferred from
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.01.030. * Corresponding author. Box 102002, 10 Bryan Searle Drive, 471 Seeley G. Mudd Building, Durham, NC 27710, USA. Tel. +1 919 668 4667; Fax: +1 919 660 0178. E-mail address: [email protected] (M.R. Harrison). http://dx.doi.org/10.1016/j.eururo.2014.02.032 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Harrison MR, Armstrong AJ. Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.02.032
EURURO-5546; No. of Pages 3 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
these data. Other agents commonly used in contemporary practice, such as enzalutamide, prednisone, and older agents such as ketoconazole or older antiandrogens, would be reasonable controls in a large population-based comparative effectiveness study. In the COU-AA-301 study, there was no statistically significant difference in survival between the AA plus prednisone and the prednisone-alone arms in PS 2 patients (7.3 vs 7.0 mo; hazard ratio [HR]: 0.81 [0.53– 1.24]). However, this study lacked the power to demonstrate such a difference, as these men represented only 127 of 1195 in the trial. Some data to shed light on this question were provided by a recent meta-analysis of post–docetaxel treatments in men with ECOG PS 2 [7]. In this meta-analysis, which included data from TROPIC, COU-AA-301, and AFFIRM (n = 3149), the 290 patients (9.2%) with PS 2 had a reduced risk of death by 26% (HR: 0.74 [0.56–0.98]; p = 0.035) with the experimental treatments (cabazitaxel, AA, and enzalutamide) compared with the controls. A related question is, If patients with PS 2 do not derive benefit from AA, with what agent(s) should they be treated instead? These questions will ultimately require a prospective randomized trial to be answered. Clearly, predictive biomarkers of AA efficacy, which currently do not exist, would be helpful in identifying patients most likely to benefit. Although the authors state that close monitoring and early treatment with AA may result in better outcomes, there are no data in the manuscript that directly support this statement. We know that patients with mCRPC generally proceed from asymptomatic to minimally symptomatic to overtly symptomatic states with concurrently declining PS. The PS, like PSA, pain, and many other clinical factors, is simply a manifestation of increasing burden of disease, among other things. Factors related to disease burden have proven important in selecting groups with greater survival in pivotal trials of all approved therapies in mCRPC (immunotherapy, chemotherapy, radiopharmaceuticals, and androgen receptor–targeted therapies). For example, a retrospective analysis of the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study (sipuleucel-T) demonstrated greater improvement in overall survival (OS) in patients in the lowest PSA quartile compared with higher quartiles [8]. In TAX-327 (docetaxel), men without pain received more cycles and greater OS benefit than men with pain, while absolute PSA level and PSA kinetics also had prognostic value [9]. In the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial (radium 223), patients with and ECOG PS of 0–1 had a greater survival advantage than patients with an ECOG PS of 2 [10]. As has been mentioned, LDH and alkaline phosphatase may also be markers of disease burden and have proven prognostic with multiple therapies, and alkaline phosphatase may be predictive of Ra 223 benefit. So we know that disease burden matters in mCRPC, and in some cases, related biomarkers can be helpful in determining the appropriate timing of treatment and selection of patients. From this manuscript, we might deduce that by monitoring a patient more closely, perhaps with more
frequent imaging studies and/or clinic visits, a drug like AA might be started when a patient is asymptomatic to minimally symptomatic rather than overtly symptomatic and hence result in better outcomes. In particular, the 38% of patients who were both ECOG PS 2 and docetaxel-naive might have been targeted for closer monitoring and intervention before deterioration in PS. One barrier to this monitoring may be the transition from the urologist or radiation oncologist to the medical oncologist. It is only in the last 10 yr that systemic therapy in mCRPC has been shown to extend survival. Multiple life-prolonging systemic therapies have been approved in the last 3–4 yr. Urologists or radiation oncologists who do not stay apprised of changes in the treatment landscape of mCRPC and update their practice patterns may delay their referrals of patients or delay the initiation of proven therapies, thus missing a window for treatment when the disease burden is low. With a multitude of active therapies recently added to the armamentarium, urologists, radiation oncologists, and medical oncologists working together cooperatively as a multidisciplinary team has never been more important in mCRPC. Conflicts of interest: Andrew J. Armstrong has received research funding from Medivation, Inc., Janssen, Sanofi-Aventis, and Dendreon and speaker honoraria from Dendreon; he has been a consultant for Bayer-Algeta, Medivation, Janssen, Sanofi-Aventis, and Dendreon; and he receives funding from the Robert B. Goergen Prostate Cancer Foundation Young Investigator Award (A.J. Armstrong) and the Department of Defense Physician Research Training Award W81XWH10–1-0483. Michael R. Harrison has received research funding from Medivation, Inc. Dendreon, and Janssen and speaker honoraria from Dendreon; he has been a consultant for Sanofi-Aventis, Exelixis, and Dendreon.
References [1] Azad AA, Eigl BJ, Leibowitz-Amit R, et al. Outcomes with abiraterone acetate in metastatic castration-resistant prostate cancer patients who have poor performance status. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2014.01.030 [2] Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003;21:1232–7. [3] Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 2010;16:203–11. [4] Smaletz O, Scher HI, Small EJ, et al. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol 2002;20:3972–82. [5] Halabi S, Lin CY, Small EJ, et al. Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy. J Natl Cancer Inst 2013;105: 1729–37. [6] Chi KN, Kheoh TS, Ryan CJ, et al. A prognostic model for predicting overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) after docetaxel [abstract 5013]. J Clin Oncol 2013;31(Suppl). [7] Iacovelli R, Altavilla A, Procopio G, et al. Are post-docetaxel treatments effective in patients with castration-resistant prostate cancer
Please cite this article in press as: Harrison MR, Armstrong AJ. Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.02.032
EURURO-5546; No. of Pages 3 EUROPEAN UROLOGY XXX (2014) XXX–XXX
and performance of 2? a meta-analysis of published trials. Prostate Cancer Prostatic Dis 2013;16:323–7. [8] Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the
3
[9] Armstrong AJ, Garrett-Mayer ES, Yang YC, de Wit R, Tannock IF, Eisenberger M. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res 2007;13:6396–403. [10] Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and
Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT)
survival in metastatic prostate cancer. N Engl J Med 2013;369:
trial. Urology 2013;81:1297–302.
213–23.
Please cite this article in press as: Harrison MR, Armstrong AJ. Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.02.032
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer Michael R. Harrison a,*, Andrew J. Armstrong a,b a
Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; b Department of Surgery, Duke Cancer Institute, Duke
University Medical Center, Durham, NC, USA
In this issue of European Urology, Azad et al. report on the real-world experience in Canada of men with metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen synthesis inhibitor abiraterone acetate (AA) with prednisone [1]. The investigators focused on men with poor functional status as determined by the Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, given that patients with poor functional status were underrepresented in the phase 3 trials of AA and are actually more likely to receive this agent in practice compared with taxane-based chemotherapy for multiple reasons. Functional status can be determined by a number of host and tumor-specific factors, ranging from comorbidities and age to prior therapies, neuropathy, anemia, cancerrelated fatigue, or pain. The authors analyzed a number of prognostic factors, including prior castration sensitivity, the pattern of metastatic spread, and biomarkers such as lactate dehydrogenase (LDH), alkaline phosphatase, hemoglobin, and prostate-specific antigen (PSA); in the end, PS was clearly an important and independent factor in determining response and survival with AA in this population. What does this paper do to advance our knowledge and treatment decision making? The authors are to be commended for conducting this study in a population of mCRPC patients for whom there is currently a paucity of data: patients with ECOG PS 2. As drugs are approved, they are commonly used in broader populations than those included in clinical trials. AA, in particular, may be used in real-world patients with poorer PS preferentially over chemotherapies because of AA’s relatively tolerable adverse effect profile. As the authors
point out, only 10% of patients in the COU-AA-301 (after docetaxel) study had PS 2, and by design, none of the patients in the COU-AA-302 (before docetaxel) study had PS 2. In contrast, approximately 40% of this Canadian cohort had PS 2, and 38% of this group was docetaxel-naive. The reasons for this large difference between the clinical trial and real-world populations are not entirely clear but likely reflect decisions made in the pivotal clinical trial designs to enrich for patients most likely to benefit from and least likely to be harmed by AA. Both the docetaxelpretreated and docetaxel-naive groups had inferior outcomes in patients with PS 2 compared with PS 0–1. PS remained a significant prognostic factor even with inclusion of post–abiraterone systemic therapy, which was more frequent in the PS 0–1 group, in the multivariate model. These results are not entirely surprising, as baseline PS is known to be prognostic in multiple settings in mCRPC, both before chemotherapy [2–4] and after chemotherapy [5]. PS 2 was identified as a factor associated with a poor prognosis in the COU-AA-301 trial [6]. Deterioration in PS reflects a range of host factors including comorbidity, but it also is reflective of a higher disease burden and more aggressive and disseminated disease; this more aggressive tumor phenotype may be more likely to have redundant pathways and develop resistance more quickly to systemic therapy. Unfortunately, one of the most interesting clinical questions—whether patients with PS 2 derive a survival benefit from AA—cannot be answered by this study. Despite the poor outcomes for patients with PS 2, there was no comparator arm; thus, the conclusion that these patients derive little or no benefit from AA cannot be inferred from
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.01.030. * Corresponding author. Box 102002, 10 Bryan Searle Drive, 471 Seeley G. Mudd Building, Durham, NC 27710, USA. Tel. +1 919 668 4667; Fax: +1 919 660 0178. E-mail address: [email protected] (M.R. Harrison). http://dx.doi.org/10.1016/j.eururo.2014.02.032 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Harrison MR, Armstrong AJ. Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.02.032
EURURO-5546; No. of Pages 3 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
these data. Other agents commonly used in contemporary practice, such as enzalutamide, prednisone, and older agents such as ketoconazole or older antiandrogens, would be reasonable controls in a large population-based comparative effectiveness study. In the COU-AA-301 study, there was no statistically significant difference in survival between the AA plus prednisone and the prednisone-alone arms in PS 2 patients (7.3 vs 7.0 mo; hazard ratio [HR]: 0.81 [0.53– 1.24]). However, this study lacked the power to demonstrate such a difference, as these men represented only 127 of 1195 in the trial. Some data to shed light on this question were provided by a recent meta-analysis of post–docetaxel treatments in men with ECOG PS 2 [7]. In this meta-analysis, which included data from TROPIC, COU-AA-301, and AFFIRM (n = 3149), the 290 patients (9.2%) with PS 2 had a reduced risk of death by 26% (HR: 0.74 [0.56–0.98]; p = 0.035) with the experimental treatments (cabazitaxel, AA, and enzalutamide) compared with the controls. A related question is, If patients with PS 2 do not derive benefit from AA, with what agent(s) should they be treated instead? These questions will ultimately require a prospective randomized trial to be answered. Clearly, predictive biomarkers of AA efficacy, which currently do not exist, would be helpful in identifying patients most likely to benefit. Although the authors state that close monitoring and early treatment with AA may result in better outcomes, there are no data in the manuscript that directly support this statement. We know that patients with mCRPC generally proceed from asymptomatic to minimally symptomatic to overtly symptomatic states with concurrently declining PS. The PS, like PSA, pain, and many other clinical factors, is simply a manifestation of increasing burden of disease, among other things. Factors related to disease burden have proven important in selecting groups with greater survival in pivotal trials of all approved therapies in mCRPC (immunotherapy, chemotherapy, radiopharmaceuticals, and androgen receptor–targeted therapies). For example, a retrospective analysis of the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study (sipuleucel-T) demonstrated greater improvement in overall survival (OS) in patients in the lowest PSA quartile compared with higher quartiles [8]. In TAX-327 (docetaxel), men without pain received more cycles and greater OS benefit than men with pain, while absolute PSA level and PSA kinetics also had prognostic value [9]. In the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial (radium 223), patients with and ECOG PS of 0–1 had a greater survival advantage than patients with an ECOG PS of 2 [10]. As has been mentioned, LDH and alkaline phosphatase may also be markers of disease burden and have proven prognostic with multiple therapies, and alkaline phosphatase may be predictive of Ra 223 benefit. So we know that disease burden matters in mCRPC, and in some cases, related biomarkers can be helpful in determining the appropriate timing of treatment and selection of patients. From this manuscript, we might deduce that by monitoring a patient more closely, perhaps with more
frequent imaging studies and/or clinic visits, a drug like AA might be started when a patient is asymptomatic to minimally symptomatic rather than overtly symptomatic and hence result in better outcomes. In particular, the 38% of patients who were both ECOG PS 2 and docetaxel-naive might have been targeted for closer monitoring and intervention before deterioration in PS. One barrier to this monitoring may be the transition from the urologist or radiation oncologist to the medical oncologist. It is only in the last 10 yr that systemic therapy in mCRPC has been shown to extend survival. Multiple life-prolonging systemic therapies have been approved in the last 3–4 yr. Urologists or radiation oncologists who do not stay apprised of changes in the treatment landscape of mCRPC and update their practice patterns may delay their referrals of patients or delay the initiation of proven therapies, thus missing a window for treatment when the disease burden is low. With a multitude of active therapies recently added to the armamentarium, urologists, radiation oncologists, and medical oncologists working together cooperatively as a multidisciplinary team has never been more important in mCRPC. Conflicts of interest: Andrew J. Armstrong has received research funding from Medivation, Inc., Janssen, Sanofi-Aventis, and Dendreon and speaker honoraria from Dendreon; he has been a consultant for Bayer-Algeta, Medivation, Janssen, Sanofi-Aventis, and Dendreon; and he receives funding from the Robert B. Goergen Prostate Cancer Foundation Young Investigator Award (A.J. Armstrong) and the Department of Defense Physician Research Training Award W81XWH10–1-0483. Michael R. Harrison has received research funding from Medivation, Inc. Dendreon, and Janssen and speaker honoraria from Dendreon; he has been a consultant for Sanofi-Aventis, Exelixis, and Dendreon.
References [1] Azad AA, Eigl BJ, Leibowitz-Amit R, et al. Outcomes with abiraterone acetate in metastatic castration-resistant prostate cancer patients who have poor performance status. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2014.01.030 [2] Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003;21:1232–7. [3] Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 2010;16:203–11. [4] Smaletz O, Scher HI, Small EJ, et al. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol 2002;20:3972–82. [5] Halabi S, Lin CY, Small EJ, et al. Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy. J Natl Cancer Inst 2013;105: 1729–37. [6] Chi KN, Kheoh TS, Ryan CJ, et al. A prognostic model for predicting overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) after docetaxel [abstract 5013]. J Clin Oncol 2013;31(Suppl). [7] Iacovelli R, Altavilla A, Procopio G, et al. Are post-docetaxel treatments effective in patients with castration-resistant prostate cancer
Please cite this article in press as: Harrison MR, Armstrong AJ. Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.02.032
EURURO-5546; No. of Pages 3 EUROPEAN UROLOGY XXX (2014) XXX–XXX
and performance of 2? a meta-analysis of published trials. Prostate Cancer Prostatic Dis 2013;16:323–7. [8] Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the
3
[9] Armstrong AJ, Garrett-Mayer ES, Yang YC, de Wit R, Tannock IF, Eisenberger M. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res 2007;13:6396–403. [10] Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and
Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT)
survival in metastatic prostate cancer. N Engl J Med 2013;369:
trial. Urology 2013;81:1297–302.
213–23.
Please cite this article in press as: Harrison MR, Armstrong AJ. Burden of Disease Matters When It Comes to Systemic Therapy for Prostate Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.02.032
