Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302

Relationship between patient-reported outcomes and clinical outcomes in metastatic... Abstract Background Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC). Patients and methods We investigated relationships between changes in self-reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self-reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression. Results In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P < 0.0001). In multivariate models, all except pain intensity remained associated with OS. Pain intensity, PWB and FWB improvements remained associated with rPFS. In COU-AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P ≤ 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results. Conclusions PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression. metastatic castration-resistant prostate cancer, overall survival, pain, patient-reported outcomes, quality of life, radiographic progression-free survival Key Message In an analysis of two randomized, phase III clinical trials in metastatic castration-resistant prostate cancer (mCRPC), changes in patient-reported outcomes (PROs) were significantly correlated with clinically relevant efficacy outcomes. PROs may complement traditional clinical practice methods for monitoring disease progression in mCRPC patients and may inform treatment decision-making. Introduction In many patients with metastatic castration-resistant prostate cancer (mCRPC), complications from metastases and treatment-related toxicities can lead to rapid onset of pain, fatigue, and diminished physical well-being (PWB) and functional well-being (FWB), which can have a negative impact on overall health-related quality of life (HRQoL) [1, 2]. Studies in a wide variety of malignancies demonstrate the prognostic value of patient-reported outcomes (PROs) measured at baseline [3]. However, the association between postbaseline changes in PRO measures and clinical outcomes is not known. Thus, evaluation of changes in PROs is important for establishing an improved clinical understanding of a patient’s cancer experience and treatment. A modification of the Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve reporting of PRO data from clinical trials. The CONSORT PRO extension was designed to facilitate meaningful interpretation of trial results and better inform therapeutic decision-making and patient care [4]. PROs are becoming increasingly important in cancer drug development [5], and several treatments for mCRPC (abiraterone acetate plus prednisone, cabazitaxel, enzalutamide and radium-223) now include PRO label claims approved by regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency [1]. Although PROs have been assessed in several recent mCRPC clinical trials in the chemotherapy-naïve and postdocetaxel settings [6–8], their relationship with clinical outcomes has not been well studied. Healthcare providers, payers and patients are interested in the clinical meaningfulness of self-reported symptoms, which may affect treatment decision-making and future healthcare costs [9]. COU-AA-301 (clinicaltrials.gov: NCT00638690) and COU-AA-302 (clinicaltrials.gov: NCT00887198) were international, phase III, randomized, double-blind trials of abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) (hereafter abiraterone–prednisone) versus placebo plus prednisone (hereafter prednisone alone) in postdocetaxel or chemotherapy-naïve patients with mCRPC, respectively [10, 11]. COU-AA-301 enrolled 1195 patients (n = 797 abiraterone–prednisone; n = 398 prednisone alone) who had progressed after docetaxel-based chemotherapy and had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 [10]. COU-AA-302 enrolled 1088 patients (n = 546 abiraterone–prednisone; n = 542 prednisone alone) who had no prior chemotherapy, were asymptomatic [score, 0 or 1 on Brief Pain Inventory-Short Form (BPI-SF) item 3] or mildly symptomatic (score, 2 or 3 on BPI-SF item 3), had ECOG PS 0 or 1 and had no prior visceral metastases [11]. The relationships between changes in PROs and subsequent clinical outcomes [overall survival (OS) and radiographic progression-free survival (rPFS)] were explored using the COU-AA-301 and COU-AA-302 datasets. In both trials, tumor assessments and PRO data were collected with regular frequency as prespecified time points in the study protocol. This posthoc analysis was designed to determine whether there was a consistent relationship between changes in PROs and subsequent clinical outcomes. Since PRO questionnaires can be administered with greater frequency and less invasively than tumor assessments, changes in PROs have the potential to inform diagnostic and treatment decisions. Patients in COU-AA-301 were in poorer health at baseline than those in COU-AA-302 (Table 1). Therefore, the relationship between clinical outcomes and PROs was assessed in a manner suited to each patient population. In patients from COU-AA-301, the association between PRO improvements and clinical outcomes was evaluated; in patients from COU-AA-302, the association between PRO worsening and clinical outcomes was assessed. Table 1. Baseline patient demographic, clinical and patient-reported outcome (PRO) characteristics Baseline characteristic  COU-AA-301  COU-AA-302    N = 1195  N = 1088  Age, years   Median (IQR)  69 (64–75)  70 (64–77)  Race, n (%)   White  1111/1193 (93)  1030/1085 (95)   Black  43/1193 (4)  28/1085 (3)   Asian  20/1193 (2)  13/1085 (1)   American Indian or Alaska native  3/1193 (<1)  0   Other  16/1193 (1)  14/1085 (1)  Baseline serum PSA, ng/ml   Median (IQR)  131.4 (42.4–423.0)  39.5 (15.6–106.5)  Gleason score at initial diagnosis, n (%)   ≤7  502/1047 (48)  479/1047 (48)   ≥8  545/1047 (52)  517/1047 (52)    N = 1190  N = 1086  Extent of disease, n (%)   Bone  1066/1190 (90)  884/1086 (81)   Bone only  474/1190 (40)  541/1086 (50)   Soft tissue or node  709/1190 (60)  538/1086 (50)   Other  60/1190 (5)  11/1086 (1)  ECOG PS, n (%)   0 or 1  1068/1195 (89)  1088/1088 (100)   2  127/1195 (11)  0  Number of prior therapies, n (%)   0  0  2 (<1)   1  1/1195 (<1)  276 (25)   2  172/1195 (14)  439 (40)   3  568/1195 (48)  321 (30)   4  454/1195 (38)  50 (5)  Number of prior lines of chemotherapy, n (%)   1  833/1195 (70)  0   2  362/1195 (30)  0  Time from initial diagnosis to first dose, days   Median (IQR)  2198 (1223–3563)  1935 (995–3517)  Geographic region, n (%)       United States  498/1195 (42)  472/1088 (43)   Canada  154/1195 (13)  100/1088 (9)   Europe  439/1195 (37)  384/1088 (35)   Australia  104/1195 (9)  132/1088 (12)  Baseline PRO score, mean (SD)   Fatigue intensity  3.7 (2.5)  –   Pain intensity  2.4 (2.0)  0.8 (1.1)   FWB  17.0 (6.0)  21.4 (5.3)   PWB  20.4 (5.5)  25.2 (3.1)   PCS  29.7 (7.5)  35.2 (6.0)  Baseline characteristic  COU-AA-301  COU-AA-302    N = 1195  N = 1088  Age, years   Median (IQR)  69 (64–75)  70 (64–77)  Race, n (%)   White  1111/1193 (93)  1030/1085 (95)   Black  43/1193 (4)  28/1085 (3)   Asian  20/1193 (2)  13/1085 (1)   American Indian or Alaska native  3/1193 (<1)  0   Other  16/1193 (1)  14/1085 (1)  Baseline serum PSA, ng/ml   Median (IQR)  131.4 (42.4–423.0)  39.5 (15.6–106.5)  Gleason score at initial diagnosis, n (%)   ≤7  502/1047 (48)  479/1047 (48)   ≥8  545/1047 (52)  517/1047 (52)    N = 1190  N = 1086  Extent of disease, n (%)   Bone  1066/1190 (90)  884/1086 (81)   Bone only  474/1190 (40)  541/1086 (50)   Soft tissue or node  709/1190 (60)  538/1086 (50)   Other  60/1190 (5)  11/1086 (1)  ECOG PS, n (%)   0 or 1  1068/1195 (89)  1088/1088 (100)   2  127/1195 (11)  0  Number of prior therapies, n (%)   0  0  2 (<1)   1  1/1195 (<1)  276 (25)   2  172/1195 (14)  439 (40)   3  568/1195 (48)  321 (30)   4  454/1195 (38)  50 (5)  Number of prior lines of chemotherapy, n (%)   1  833/1195 (70)  0   2  362/1195 (30)  0  Time from initial diagnosis to first dose, days   Median (IQR)  2198 (1223–3563)  1935 (995–3517)  Geographic region, n (%)       United States  498/1195 (42)  472/1088 (43)   Canada  154/1195 (13)  100/1088 (9)   Europe  439/1195 (37)  384/1088 (35)   Australia  104/1195 (9)  132/1088 (12)  Baseline PRO score, mean (SD)   Fatigue intensity  3.7 (2.5)  –   Pain intensity  2.4 (2.0)  0.8 (1.1)   FWB  17.0 (6.0)  21.4 (5.3)   PWB  20.4 (5.5)  25.2 (3.1)   PCS  29.7 (7.5)  35.2 (6.0)  ECOG PS, Eastern Cooperative Oncology Group performance status; FWB, functional well-being; IQR, interquartile range; PCS, prostate cancer subscale; PSA, prostate-specific antigen; PWB, physical well-being; SD, standard deviation. Methods Patient population This posthoc analysis included all patients from COU-AA-301 and COU-AA-302, regardless of treatment arm. Prognostic index models by treatment arm have been described for both studies [12, 13]. The study was conducted according to principles of the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference on Harmonisation. All patients provided written informed consent to participate. Methods Relationships between changes in self-reported fatigue (COU-AA-301 only), pain, FWB, PWB and prostate cancer-specific symptoms with clinical time-to-event outcomes (OS and rPFS) were assessed using data from the first 6 months of treatment. Since PROs were not assessed beyond disease progression, the 6-month post-treatment time point was selected because of the likelihood that PRO and clinical data would be available for the largest number of patients. An additional sensitivity analysis was conducted using data from 12 months post-treatment to confirm these results. In both studies, OS was defined as the time from randomization to death from any cause and radiographic progression was defined as soft-tissue disease progression according to modified Response Evaluation Criteria in Solid Tumors (with a baseline lymph node of ≥2.0 cm considered a target lesion) or progression according to bone scans revealing two or more new lesions not consistent with tumor flare. Assessment of rPFS in COU-AA-302 included blinded, independent review of all scheduled and unscheduled tumor response (computed tomography and magnetic resonance imaging) and bone progression (bone scan) data. Patients completed PRO questionnaires independently during scheduled office visits. Fatigue (COU-AA-301 only) was assessed using the Brief Fatigue Inventory [BFI [14]; average of items 1 (present fatigue), 2 (usual fatigue level in last 24 h) and 3 (worst fatigue in last 24 h)], with a score range of 0–10 for each. A higher BFI score indicates worse fatigue. Pain was assessed using the BPI-SF [15]: average of items 3 (worst pain in last 24 h), 4 (least pain in last 24 h), 5 (average pain) and 6 (present pain), with a score range of 0–10 for each. Higher BPI-SF score indicates worse pain intensity. Prostate-specific HRQoL, including pain and fatigue, was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire [16]. The following scores, derived from the FACT-P, were included in this analysis because they bear conceptual relationship to clinical variables of progression and survival: FWB [subscale of FACT-General (FACT-G)] (score range, 0–28), PWB (subscale of FACT-G) (score range, 0–28) and Prostate Cancer Subscale (PCS) (score range, 0–48). Higher scores in each indicate better FWB, PWB or prostate cancer-specific signs and symptoms, respectively (supplementary Appendix S1, available at Annals of Oncology online). While absolute values of the threshold criteria applied were consistent for both studies, the direction of the change measured (improvement or worsening) was specific to the patient population. In COU-AA-301, the threshold criterion for PRO improvements for fatigue intensity and pain intensity was a decrease ≥2 points from baseline. The threshold criterion for improvement in PWB, FWB and PCS was an increase ≥4 points from baseline. In COU-AA-302, the threshold criterion for PRO worsening in pain intensity was an increase ≥2 points from baseline; the threshold for worsening in FWB, PWB and PCS was a decrease ≥4 points from baseline. These thresholds were selected because they have been shown to reflect clinically meaningful change [16]. Statistical methods for PRO analyses of COU-AA-301 and COU-AA-302 To model the relationship between change in PRO score and time to event of interest, Cox proportional hazards regressions were used. The primary analysis was restricted to data from the first 6 months post-treatment; patients who had not died or progressed radiographically at the time of this cutoff were censored. Changes in PRO scores were entered into the model as binary indicator variables and to reflect whether the threshold criteria were met at any point in the first 6 months of follow-up or post-treatment. Each model was adjusted for age, baseline prostate-specific antigen, Gleason score at initial diagnosis, baseline ECOG PS score, number of prior therapies, number of prior lines of chemotherapy (COU-AA-301 only), time from diagnosis to randomization, geographic region and baseline PRO scores. In the multivariate analysis, each covariate was forced into the model, then a forward selection method was carried out on the PRO indicator variables. A significance level of 0.05 was required for entry into the multivariate model. Results Baseline characteristics were well balanced between the patient populations (Table 1, supplementary Table S1, available at Annals of Oncology online). Six-month results from COU-AA-301 At 6 months post-treatment, there were 213 deaths and 641 radiographic progression events; remaining patients were censored. In each individual model, patients with PRO score improvements had a more favorable clinical time-to-event outcome for OS and rPFS [hazard ratio (HR) < 1] during follow-up versus patients who did not improve. Improvements in fatigue intensity, pain intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to OS (P < 0.0001; Figure 1A) and rPFS (P < 0.0001; Figure 1B). Figure 1. View largeDownload slide Association between individual patient-reported outcomes (PROs) and overall survival (OS) (A) and radiographic progression-free survival (rPFS) (B) in COU-AA-301. CI, confidence interval; FWB, functional well-being; PCS, prostate cancer subscale; PWB, physical well-being. Figure 1. View largeDownload slide Association between individual patient-reported outcomes (PROs) and overall survival (OS) (A) and radiographic progression-free survival (rPFS) (B) in COU-AA-301. CI, confidence interval; FWB, functional well-being; PCS, prostate cancer subscale; PWB, physical well-being. When PRO indicators were analyzed using a forward selection approach, all except pain intensity were significantly associated with OS and added to the multivariate model. Improvements in fatigue intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to 68% (P < 0.001), 44% (P = 0.04), 61% (P = 0.006) and 59% (P < 0.001) reductions in risk of death, respectively. For rPFS, pain intensity, FWB and PWB, improvements were significantly associated with delayed radiographic progression and were added to the multivariate model. Improvements in pain intensity, FWB and PWB corresponded to 33% (P = 0.002), 30% (P = 0.006) and 39% (P < 0.001) reductions in risk of rPFS, respectively. Fatigue intensity and prostate cancer-specific signs and symptoms did not meet the statistical criteria and were not added to the model. Twelve-month results from COU-AA-301 There were 511 deaths and 884 radiographic progression events post-treatment. In each individual model, patients with PRO score improvements (supplementary Table S2, available at Annals of Oncology online) had a reduced risk of death and radiographic progression compared with patients who did not have PRO score improvements. Improvements in fatigue intensity, pain intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to 73%, 59%, 70%, 74% and 66% reductions in risk of death, respectively (P < 0.0001 each). Reductions in risk of radiographic progression were 46%, 47%, 49%, 55% and 42% for these same respective PRO indicators (P < 0.0001 each). In the multivariate analysis, all PRO indicators except pain intensity were significantly associated with OS and were added to the model (supplementary Table S3, available at Annals of Oncology online). Fatigue intensity, pain intensity, FWB and PWB improvements were significantly associated with delayed radiographic progression and were added to the model. Prostate cancer-specific signs and symptoms did not meet the criteria and were not added to the model at either 6 or 12 months post-treatment. Compared with patients whose PRO score did not worsen, patients with PRO score worsening had an increased risk of death and radiographic progression at 6 and 12 months post-treatment (supplementary Table S4, available at Annals of Oncology online). However, these associations were not as strong as those with PRO score improvements and reduced risk of death and radiographic progression. Six-month results from COU-AA-302 There were 26 deaths and 316 radiographic progression events in COU-AA-302, and too few deaths within 6 months of follow-up or post-treatment to explore the relationship between PRO and OS. In individual models, patients with PRO score worsening had a significantly higher risk (HR > 1) of radiographic progression during follow-up versus patients with no PRO score worsening. Worsening pain intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to 68% (P = 0.0002), 35% (P = 0.0249), 108% (P < 0.0001) and 52% (P = 0.0011) higher risk of radiographic progression per investigator review (Figure 2). Figure 2. View largeDownload slide Association between individual PROs and rPFS in COU-AA-302. Figure 2. View largeDownload slide Association between individual PROs and rPFS in COU-AA-302. In the multivariate analysis, only worsening PWB was significantly (P < 0.001) associated with increased risk of radiographic progression. Other PRO measures did not meet the statistical criteria for addition to the model. Twelve-month results from COU-AA-302 Post-treatment there were 99 deaths and 573 radiographic progression events. In individual models, patients with worsening PWB had a 97% higher risk of death versus patients who did not (P = 0.0019). Patients with PRO score worsening had an increased risk of radiographic progression compared with patients who did not have PRO score worsening at 12 months. Increases in risk of radiographic progression were 33% (P = 0.0046), 27% (P = 0.1086), 56% (P < 0.0001) and 22% (P = 0.0525) for pain intensity, FWB, PWB and prostate cancer signs and symptoms, respectively (supplementary Table S2, available at Annals of Oncology online). In the multivariate analysis, PWB, the only PRO indicator in COU-AA-302 significantly associated with radiographic progression at 6 months, remained significantly associated with radiographic progression at 12 months post-treatment (supplementary Table S3, available at Annals of Oncology online). Although a multivariate analysis was not conducted for OS in COU-AA-302 at 6 months, results at 12 months post-treatment were similar to those seen for radiographic progression in that only PWB worsening was added to the model. All other indicators did not meet the criteria and were not added to the models. Baseline PRO scores also corresponded to OS and rPFS at 6 months post-treatment (supplementary Table S5, available at Annals of Oncology online); however, the associations were more significant when using change in PRO scores. We then explored the relationship between changes in prognostic laboratory values (hemoglobin, alkaline phosphatase and lactate dehydrogenase) and time-to-event outcome for OS and rPFS. In both studies, a worsening in laboratory values was associated with shorter OS and rPFS at 6 and 12 months post-treatment (supplementary Tables S6 and S7, available at Annals of Oncology online). However, the best HRs were no better than the best HRs described above for changes in PROs. Similarly, improvement in laboratory values was associated with reduced risk of death and radiographic progression at 6 and 12 months in COU-AA-301 (supplementary Table S8, available at Annals of Oncology online), but the best HRs were no better than the best HRs observed for changes in PROs. Discussion Results from this analysis demonstrate a relationship between PROs and clinical outcomes in mCRPC. Patients with improved symptom reports during the first 6–12 months were less likely to experience early disease progression or death. The reverse was also true: patients with worsening symptom reports were more likely to experience shortened time to progression or death. This relationship was demonstrated in postdocetaxel as well as chemotherapy-naïve patients—particularly notable because some PRO scores, such as pain prevalence and severity, are typically worse among patients with prior docetaxel exposure and more advanced disease [17]. For example, the mean baseline pain intensity score for the COU-AA-301 population, who had more advanced disease at baseline, was 2.4, whereas it was 0.8 for the COU-AA-302 population, who were asymptomatic or mildly symptomatic at baseline. PRO indicators that were most significantly indicative of clinical outcomes could provide information to treating physicians and payers on the efficacy and efficiency of healthcare. In the postchemotherapy mCRPC population, these indicators were fatigue intensity, FWB, PWB and prostate cancer-specific signs and symptoms for OS, and pain intensity, FWB and PWB for rPFS. In the chemotherapy-naïve mCRPC patients, PWB was most significantly indicative of rPFS. The relationship between PROs and outcome was detected early: there was a significant association between PROs and improved survival and/or rPFS within 6 months post-treatment. Demonstrating an association between PROs and clinical outcomes early in the treatment course might have beneficial clinical implications, since physicians would be able to consider the clinical significance of their patients’ self-reported perspectives and thus better inform diagnostic and treatment decisions that could enhance utilization of resources and thereby positively affect overall healthcare costs. The 12-month post-treatment sensitivity analyses confirmed that the relationships between PROs and outcomes established at 6 months persisted with longer follow-up. The updated recommendations from the Prostate Cancer Clinical Trials Working Group 3 introduce the ‘no longer clinically benefitting’ reporting metric, which provides actionable recommendations to assist provider-patient decisions regarding treatment discontinuation or change based on therapeutic objectives such as QoL, PROs or survival [18]. To this end, PRO data are increasingly important as healthcare systems across the world move toward a more value-based care approach to patient management [19]. This analysis has important limitations. Clinical trial recruitment is subject to selection bias. Therefore, our study sample may not be representative of all patients with mCRPC. Moreover, there were very few non-Caucasian patients enrolled in these studies (<10%) so the validity of these results in minority populations requires further study. The exploratory nature of these analyses would benefit from replication in subsequent research with a new sample. Finally, although caregiver-reported outcomes were not obtained, they may further serve to inform future diagnostic and treatment decision-making. Conclusions This study is the first to demonstrate the relationship between changes in PROs and clinical outcomes in patients with mCRPC. The results demonstrate that not only are PROs useful in describing patient-relevant outcomes in clinical trials, they hold promise for complementing traditional clinical practice methods for monitoring patients with mCRPC throughout the course of their disease. Acknowledgements Writing assistance was provided by Lashon Pringle, PhD, and Ann Tighe, PhD, of PAREXEL and was funded by Janssen Global Services, LLC. Funding Janssen Research & Development (no grant number applies). The sponsor played a role in the design and conduct of the study; in the collection, management, analysis, and interpretation of data; and in the preparation, review, and approval of the manuscript. Disclosure DC is a consultant to Abbvie, Astellas, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Inc, Evidera, GlaxoSmithKline, Helsinn, Ipsen, Janssen Research & Development and Novartis, and is the president of FACIT.org. ST and TL are employees of Janssen Global Services and hold stock in Johnson & Johnson. KJ and AM were employees of Janssen Global Services and held stock in Johnson & Johnson at the time of the analysis. KFH has served as a consultant to Janssen Global Services. NDS has received research funding from and has served as a consultant to Astellas Pharma, Bayer, Dendreon, Ferring Pharmaceuticals, Janssen Research & Development, Medivation and Sanofi. References 1 Clark MJ, Harris N, Griebsch I et al.   Patient-reported outcome labeling claims and measurement approach for metastatic castration-resistant prostate cancer treatments in the United States and European Union. Health Qual Life Outcomes  2014; 12( 1): 104. Google Scholar CrossRef Search ADS PubMed  2 Diels J, Hamberg P, Ford D et al.   Mapping FACT-P to EQ-5D in a large cross-sectional study of metastatic castration-resistant prostate cancer patients. Qual Life Res  2015; 24( 3): 591– 598. Google Scholar CrossRef Search ADS PubMed  3 Gotay CC, Kawamoto CT, Bottomley A, Efficace F. The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol  2008; 26: 1355– 1363. Google Scholar CrossRef Search ADS PubMed  4 Calvert M, Blazeby J, Altman DG et al.   Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA  2013; 309( 8): 814– 822. Google Scholar CrossRef Search ADS PubMed  5 Basch E, Deal AM, Kris MG et al.   Symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial. J Clin Oncol  2016; 34: 557– 565. Google Scholar CrossRef Search ADS PubMed  6 Basch E, Autio K, Ryan CJ et al.   Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. Lancet Oncol  2013; 14( 12): 1193– 1199. Google Scholar CrossRef Search ADS PubMed  7 Fizazi K, Scher HI, Miller K et al.   Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol  2014; 15( 10): 1147– 1156. Google Scholar CrossRef Search ADS PubMed  8 Loriot Y, Miller K, Sternberg CN et al.   Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol  2015; 16( 5): 509– 521. Google Scholar CrossRef Search ADS PubMed  9 Mehra M, Wu Y, Dhawan R. Healthcare resource use in advanced prostate cancer patients treated with docetaxel. J Med Econ  2012; 15( 5): 836– 843. Google Scholar CrossRef Search ADS PubMed  10 Fizazi K, Scher HI, Molina A et al.   Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol  2012; 13( 10): 983– 992. Google Scholar CrossRef Search ADS PubMed  11 Ryan CJ, Smith MR, Fizazi K et al.   Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol  2015; 16( 2): 152– 160. Google Scholar CrossRef Search ADS PubMed  12 Chi KN, Kheoh T, Ryan CJ et al.   A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. Ann Oncol  2016; 27( 3): 454– 460. Google Scholar CrossRef Search ADS PubMed  13 Ryan CJ, Kheoh T, Li J et al.   Prognostic index model for progression-free survival in chemotherapy-naive metastatic castration-resistant prostate cancer treated with abiraterone acetate plus prednisone. Clin Genitourin Cancer  2017 July 25 [epub ahead of print], doi: 10.1016/j.clgc.2017.07.014. 14 Mendoza TR, Wang XS, Cleeland CS et al.   The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer  1999; 85( 5): 1186– 1196. Google Scholar CrossRef Search ADS PubMed  15 Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore  1994; 23( 2): 129– 138. Google Scholar PubMed  16 Cella D, Nichol MB, Eton D et al.   Estimating clinically meaningful changes for the Functional Assessment of Cancer Therapy–Prostate: results from a clinical trial of patients with metastatic hormone-refractory prostate cancer. Value Health  2009; 12( 1): 124– 129. Google Scholar CrossRef Search ADS PubMed  17 Autio KA, Bennett AV, Jia X et al.   Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure. J Oncol Pract  2013; 9: 223– 229. Google Scholar CrossRef Search ADS PubMed  18 Scher HI, Morris MJ, Stadler WM et al.   Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol  2016; 34: 1402– 1418. Google Scholar CrossRef Search ADS PubMed  19 Schnipper LE, Meropol NJ. Payment for cancer care: time for a new prescription. J Clin Oncol  2014; 32( 36): 4027– 4028. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302

Loading next page...
 
/lp/ou_press/relationship-between-patient-reported-outcomes-and-clinical-outcomes-IDmj3P4Cbo
Publisher
Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
eISSN
1569-8041
D.O.I.
10.1093/annonc/mdx759
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC). Patients and methods We investigated relationships between changes in self-reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self-reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression. Results In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P < 0.0001). In multivariate models, all except pain intensity remained associated with OS. Pain intensity, PWB and FWB improvements remained associated with rPFS. In COU-AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P ≤ 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results. Conclusions PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression. metastatic castration-resistant prostate cancer, overall survival, pain, patient-reported outcomes, quality of life, radiographic progression-free survival Key Message In an analysis of two randomized, phase III clinical trials in metastatic castration-resistant prostate cancer (mCRPC), changes in patient-reported outcomes (PROs) were significantly correlated with clinically relevant efficacy outcomes. PROs may complement traditional clinical practice methods for monitoring disease progression in mCRPC patients and may inform treatment decision-making. Introduction In many patients with metastatic castration-resistant prostate cancer (mCRPC), complications from metastases and treatment-related toxicities can lead to rapid onset of pain, fatigue, and diminished physical well-being (PWB) and functional well-being (FWB), which can have a negative impact on overall health-related quality of life (HRQoL) [1, 2]. Studies in a wide variety of malignancies demonstrate the prognostic value of patient-reported outcomes (PROs) measured at baseline [3]. However, the association between postbaseline changes in PRO measures and clinical outcomes is not known. Thus, evaluation of changes in PROs is important for establishing an improved clinical understanding of a patient’s cancer experience and treatment. A modification of the Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve reporting of PRO data from clinical trials. The CONSORT PRO extension was designed to facilitate meaningful interpretation of trial results and better inform therapeutic decision-making and patient care [4]. PROs are becoming increasingly important in cancer drug development [5], and several treatments for mCRPC (abiraterone acetate plus prednisone, cabazitaxel, enzalutamide and radium-223) now include PRO label claims approved by regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency [1]. Although PROs have been assessed in several recent mCRPC clinical trials in the chemotherapy-naïve and postdocetaxel settings [6–8], their relationship with clinical outcomes has not been well studied. Healthcare providers, payers and patients are interested in the clinical meaningfulness of self-reported symptoms, which may affect treatment decision-making and future healthcare costs [9]. COU-AA-301 (clinicaltrials.gov: NCT00638690) and COU-AA-302 (clinicaltrials.gov: NCT00887198) were international, phase III, randomized, double-blind trials of abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) (hereafter abiraterone–prednisone) versus placebo plus prednisone (hereafter prednisone alone) in postdocetaxel or chemotherapy-naïve patients with mCRPC, respectively [10, 11]. COU-AA-301 enrolled 1195 patients (n = 797 abiraterone–prednisone; n = 398 prednisone alone) who had progressed after docetaxel-based chemotherapy and had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 [10]. COU-AA-302 enrolled 1088 patients (n = 546 abiraterone–prednisone; n = 542 prednisone alone) who had no prior chemotherapy, were asymptomatic [score, 0 or 1 on Brief Pain Inventory-Short Form (BPI-SF) item 3] or mildly symptomatic (score, 2 or 3 on BPI-SF item 3), had ECOG PS 0 or 1 and had no prior visceral metastases [11]. The relationships between changes in PROs and subsequent clinical outcomes [overall survival (OS) and radiographic progression-free survival (rPFS)] were explored using the COU-AA-301 and COU-AA-302 datasets. In both trials, tumor assessments and PRO data were collected with regular frequency as prespecified time points in the study protocol. This posthoc analysis was designed to determine whether there was a consistent relationship between changes in PROs and subsequent clinical outcomes. Since PRO questionnaires can be administered with greater frequency and less invasively than tumor assessments, changes in PROs have the potential to inform diagnostic and treatment decisions. Patients in COU-AA-301 were in poorer health at baseline than those in COU-AA-302 (Table 1). Therefore, the relationship between clinical outcomes and PROs was assessed in a manner suited to each patient population. In patients from COU-AA-301, the association between PRO improvements and clinical outcomes was evaluated; in patients from COU-AA-302, the association between PRO worsening and clinical outcomes was assessed. Table 1. Baseline patient demographic, clinical and patient-reported outcome (PRO) characteristics Baseline characteristic  COU-AA-301  COU-AA-302    N = 1195  N = 1088  Age, years   Median (IQR)  69 (64–75)  70 (64–77)  Race, n (%)   White  1111/1193 (93)  1030/1085 (95)   Black  43/1193 (4)  28/1085 (3)   Asian  20/1193 (2)  13/1085 (1)   American Indian or Alaska native  3/1193 (<1)  0   Other  16/1193 (1)  14/1085 (1)  Baseline serum PSA, ng/ml   Median (IQR)  131.4 (42.4–423.0)  39.5 (15.6–106.5)  Gleason score at initial diagnosis, n (%)   ≤7  502/1047 (48)  479/1047 (48)   ≥8  545/1047 (52)  517/1047 (52)    N = 1190  N = 1086  Extent of disease, n (%)   Bone  1066/1190 (90)  884/1086 (81)   Bone only  474/1190 (40)  541/1086 (50)   Soft tissue or node  709/1190 (60)  538/1086 (50)   Other  60/1190 (5)  11/1086 (1)  ECOG PS, n (%)   0 or 1  1068/1195 (89)  1088/1088 (100)   2  127/1195 (11)  0  Number of prior therapies, n (%)   0  0  2 (<1)   1  1/1195 (<1)  276 (25)   2  172/1195 (14)  439 (40)   3  568/1195 (48)  321 (30)   4  454/1195 (38)  50 (5)  Number of prior lines of chemotherapy, n (%)   1  833/1195 (70)  0   2  362/1195 (30)  0  Time from initial diagnosis to first dose, days   Median (IQR)  2198 (1223–3563)  1935 (995–3517)  Geographic region, n (%)       United States  498/1195 (42)  472/1088 (43)   Canada  154/1195 (13)  100/1088 (9)   Europe  439/1195 (37)  384/1088 (35)   Australia  104/1195 (9)  132/1088 (12)  Baseline PRO score, mean (SD)   Fatigue intensity  3.7 (2.5)  –   Pain intensity  2.4 (2.0)  0.8 (1.1)   FWB  17.0 (6.0)  21.4 (5.3)   PWB  20.4 (5.5)  25.2 (3.1)   PCS  29.7 (7.5)  35.2 (6.0)  Baseline characteristic  COU-AA-301  COU-AA-302    N = 1195  N = 1088  Age, years   Median (IQR)  69 (64–75)  70 (64–77)  Race, n (%)   White  1111/1193 (93)  1030/1085 (95)   Black  43/1193 (4)  28/1085 (3)   Asian  20/1193 (2)  13/1085 (1)   American Indian or Alaska native  3/1193 (<1)  0   Other  16/1193 (1)  14/1085 (1)  Baseline serum PSA, ng/ml   Median (IQR)  131.4 (42.4–423.0)  39.5 (15.6–106.5)  Gleason score at initial diagnosis, n (%)   ≤7  502/1047 (48)  479/1047 (48)   ≥8  545/1047 (52)  517/1047 (52)    N = 1190  N = 1086  Extent of disease, n (%)   Bone  1066/1190 (90)  884/1086 (81)   Bone only  474/1190 (40)  541/1086 (50)   Soft tissue or node  709/1190 (60)  538/1086 (50)   Other  60/1190 (5)  11/1086 (1)  ECOG PS, n (%)   0 or 1  1068/1195 (89)  1088/1088 (100)   2  127/1195 (11)  0  Number of prior therapies, n (%)   0  0  2 (<1)   1  1/1195 (<1)  276 (25)   2  172/1195 (14)  439 (40)   3  568/1195 (48)  321 (30)   4  454/1195 (38)  50 (5)  Number of prior lines of chemotherapy, n (%)   1  833/1195 (70)  0   2  362/1195 (30)  0  Time from initial diagnosis to first dose, days   Median (IQR)  2198 (1223–3563)  1935 (995–3517)  Geographic region, n (%)       United States  498/1195 (42)  472/1088 (43)   Canada  154/1195 (13)  100/1088 (9)   Europe  439/1195 (37)  384/1088 (35)   Australia  104/1195 (9)  132/1088 (12)  Baseline PRO score, mean (SD)   Fatigue intensity  3.7 (2.5)  –   Pain intensity  2.4 (2.0)  0.8 (1.1)   FWB  17.0 (6.0)  21.4 (5.3)   PWB  20.4 (5.5)  25.2 (3.1)   PCS  29.7 (7.5)  35.2 (6.0)  ECOG PS, Eastern Cooperative Oncology Group performance status; FWB, functional well-being; IQR, interquartile range; PCS, prostate cancer subscale; PSA, prostate-specific antigen; PWB, physical well-being; SD, standard deviation. Methods Patient population This posthoc analysis included all patients from COU-AA-301 and COU-AA-302, regardless of treatment arm. Prognostic index models by treatment arm have been described for both studies [12, 13]. The study was conducted according to principles of the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference on Harmonisation. All patients provided written informed consent to participate. Methods Relationships between changes in self-reported fatigue (COU-AA-301 only), pain, FWB, PWB and prostate cancer-specific symptoms with clinical time-to-event outcomes (OS and rPFS) were assessed using data from the first 6 months of treatment. Since PROs were not assessed beyond disease progression, the 6-month post-treatment time point was selected because of the likelihood that PRO and clinical data would be available for the largest number of patients. An additional sensitivity analysis was conducted using data from 12 months post-treatment to confirm these results. In both studies, OS was defined as the time from randomization to death from any cause and radiographic progression was defined as soft-tissue disease progression according to modified Response Evaluation Criteria in Solid Tumors (with a baseline lymph node of ≥2.0 cm considered a target lesion) or progression according to bone scans revealing two or more new lesions not consistent with tumor flare. Assessment of rPFS in COU-AA-302 included blinded, independent review of all scheduled and unscheduled tumor response (computed tomography and magnetic resonance imaging) and bone progression (bone scan) data. Patients completed PRO questionnaires independently during scheduled office visits. Fatigue (COU-AA-301 only) was assessed using the Brief Fatigue Inventory [BFI [14]; average of items 1 (present fatigue), 2 (usual fatigue level in last 24 h) and 3 (worst fatigue in last 24 h)], with a score range of 0–10 for each. A higher BFI score indicates worse fatigue. Pain was assessed using the BPI-SF [15]: average of items 3 (worst pain in last 24 h), 4 (least pain in last 24 h), 5 (average pain) and 6 (present pain), with a score range of 0–10 for each. Higher BPI-SF score indicates worse pain intensity. Prostate-specific HRQoL, including pain and fatigue, was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire [16]. The following scores, derived from the FACT-P, were included in this analysis because they bear conceptual relationship to clinical variables of progression and survival: FWB [subscale of FACT-General (FACT-G)] (score range, 0–28), PWB (subscale of FACT-G) (score range, 0–28) and Prostate Cancer Subscale (PCS) (score range, 0–48). Higher scores in each indicate better FWB, PWB or prostate cancer-specific signs and symptoms, respectively (supplementary Appendix S1, available at Annals of Oncology online). While absolute values of the threshold criteria applied were consistent for both studies, the direction of the change measured (improvement or worsening) was specific to the patient population. In COU-AA-301, the threshold criterion for PRO improvements for fatigue intensity and pain intensity was a decrease ≥2 points from baseline. The threshold criterion for improvement in PWB, FWB and PCS was an increase ≥4 points from baseline. In COU-AA-302, the threshold criterion for PRO worsening in pain intensity was an increase ≥2 points from baseline; the threshold for worsening in FWB, PWB and PCS was a decrease ≥4 points from baseline. These thresholds were selected because they have been shown to reflect clinically meaningful change [16]. Statistical methods for PRO analyses of COU-AA-301 and COU-AA-302 To model the relationship between change in PRO score and time to event of interest, Cox proportional hazards regressions were used. The primary analysis was restricted to data from the first 6 months post-treatment; patients who had not died or progressed radiographically at the time of this cutoff were censored. Changes in PRO scores were entered into the model as binary indicator variables and to reflect whether the threshold criteria were met at any point in the first 6 months of follow-up or post-treatment. Each model was adjusted for age, baseline prostate-specific antigen, Gleason score at initial diagnosis, baseline ECOG PS score, number of prior therapies, number of prior lines of chemotherapy (COU-AA-301 only), time from diagnosis to randomization, geographic region and baseline PRO scores. In the multivariate analysis, each covariate was forced into the model, then a forward selection method was carried out on the PRO indicator variables. A significance level of 0.05 was required for entry into the multivariate model. Results Baseline characteristics were well balanced between the patient populations (Table 1, supplementary Table S1, available at Annals of Oncology online). Six-month results from COU-AA-301 At 6 months post-treatment, there were 213 deaths and 641 radiographic progression events; remaining patients were censored. In each individual model, patients with PRO score improvements had a more favorable clinical time-to-event outcome for OS and rPFS [hazard ratio (HR) < 1] during follow-up versus patients who did not improve. Improvements in fatigue intensity, pain intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to OS (P < 0.0001; Figure 1A) and rPFS (P < 0.0001; Figure 1B). Figure 1. View largeDownload slide Association between individual patient-reported outcomes (PROs) and overall survival (OS) (A) and radiographic progression-free survival (rPFS) (B) in COU-AA-301. CI, confidence interval; FWB, functional well-being; PCS, prostate cancer subscale; PWB, physical well-being. Figure 1. View largeDownload slide Association between individual patient-reported outcomes (PROs) and overall survival (OS) (A) and radiographic progression-free survival (rPFS) (B) in COU-AA-301. CI, confidence interval; FWB, functional well-being; PCS, prostate cancer subscale; PWB, physical well-being. When PRO indicators were analyzed using a forward selection approach, all except pain intensity were significantly associated with OS and added to the multivariate model. Improvements in fatigue intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to 68% (P < 0.001), 44% (P = 0.04), 61% (P = 0.006) and 59% (P < 0.001) reductions in risk of death, respectively. For rPFS, pain intensity, FWB and PWB, improvements were significantly associated with delayed radiographic progression and were added to the multivariate model. Improvements in pain intensity, FWB and PWB corresponded to 33% (P = 0.002), 30% (P = 0.006) and 39% (P < 0.001) reductions in risk of rPFS, respectively. Fatigue intensity and prostate cancer-specific signs and symptoms did not meet the statistical criteria and were not added to the model. Twelve-month results from COU-AA-301 There were 511 deaths and 884 radiographic progression events post-treatment. In each individual model, patients with PRO score improvements (supplementary Table S2, available at Annals of Oncology online) had a reduced risk of death and radiographic progression compared with patients who did not have PRO score improvements. Improvements in fatigue intensity, pain intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to 73%, 59%, 70%, 74% and 66% reductions in risk of death, respectively (P < 0.0001 each). Reductions in risk of radiographic progression were 46%, 47%, 49%, 55% and 42% for these same respective PRO indicators (P < 0.0001 each). In the multivariate analysis, all PRO indicators except pain intensity were significantly associated with OS and were added to the model (supplementary Table S3, available at Annals of Oncology online). Fatigue intensity, pain intensity, FWB and PWB improvements were significantly associated with delayed radiographic progression and were added to the model. Prostate cancer-specific signs and symptoms did not meet the criteria and were not added to the model at either 6 or 12 months post-treatment. Compared with patients whose PRO score did not worsen, patients with PRO score worsening had an increased risk of death and radiographic progression at 6 and 12 months post-treatment (supplementary Table S4, available at Annals of Oncology online). However, these associations were not as strong as those with PRO score improvements and reduced risk of death and radiographic progression. Six-month results from COU-AA-302 There were 26 deaths and 316 radiographic progression events in COU-AA-302, and too few deaths within 6 months of follow-up or post-treatment to explore the relationship between PRO and OS. In individual models, patients with PRO score worsening had a significantly higher risk (HR > 1) of radiographic progression during follow-up versus patients with no PRO score worsening. Worsening pain intensity, FWB, PWB and prostate cancer-specific signs and symptoms corresponded to 68% (P = 0.0002), 35% (P = 0.0249), 108% (P < 0.0001) and 52% (P = 0.0011) higher risk of radiographic progression per investigator review (Figure 2). Figure 2. View largeDownload slide Association between individual PROs and rPFS in COU-AA-302. Figure 2. View largeDownload slide Association between individual PROs and rPFS in COU-AA-302. In the multivariate analysis, only worsening PWB was significantly (P < 0.001) associated with increased risk of radiographic progression. Other PRO measures did not meet the statistical criteria for addition to the model. Twelve-month results from COU-AA-302 Post-treatment there were 99 deaths and 573 radiographic progression events. In individual models, patients with worsening PWB had a 97% higher risk of death versus patients who did not (P = 0.0019). Patients with PRO score worsening had an increased risk of radiographic progression compared with patients who did not have PRO score worsening at 12 months. Increases in risk of radiographic progression were 33% (P = 0.0046), 27% (P = 0.1086), 56% (P < 0.0001) and 22% (P = 0.0525) for pain intensity, FWB, PWB and prostate cancer signs and symptoms, respectively (supplementary Table S2, available at Annals of Oncology online). In the multivariate analysis, PWB, the only PRO indicator in COU-AA-302 significantly associated with radiographic progression at 6 months, remained significantly associated with radiographic progression at 12 months post-treatment (supplementary Table S3, available at Annals of Oncology online). Although a multivariate analysis was not conducted for OS in COU-AA-302 at 6 months, results at 12 months post-treatment were similar to those seen for radiographic progression in that only PWB worsening was added to the model. All other indicators did not meet the criteria and were not added to the models. Baseline PRO scores also corresponded to OS and rPFS at 6 months post-treatment (supplementary Table S5, available at Annals of Oncology online); however, the associations were more significant when using change in PRO scores. We then explored the relationship between changes in prognostic laboratory values (hemoglobin, alkaline phosphatase and lactate dehydrogenase) and time-to-event outcome for OS and rPFS. In both studies, a worsening in laboratory values was associated with shorter OS and rPFS at 6 and 12 months post-treatment (supplementary Tables S6 and S7, available at Annals of Oncology online). However, the best HRs were no better than the best HRs described above for changes in PROs. Similarly, improvement in laboratory values was associated with reduced risk of death and radiographic progression at 6 and 12 months in COU-AA-301 (supplementary Table S8, available at Annals of Oncology online), but the best HRs were no better than the best HRs observed for changes in PROs. Discussion Results from this analysis demonstrate a relationship between PROs and clinical outcomes in mCRPC. Patients with improved symptom reports during the first 6–12 months were less likely to experience early disease progression or death. The reverse was also true: patients with worsening symptom reports were more likely to experience shortened time to progression or death. This relationship was demonstrated in postdocetaxel as well as chemotherapy-naïve patients—particularly notable because some PRO scores, such as pain prevalence and severity, are typically worse among patients with prior docetaxel exposure and more advanced disease [17]. For example, the mean baseline pain intensity score for the COU-AA-301 population, who had more advanced disease at baseline, was 2.4, whereas it was 0.8 for the COU-AA-302 population, who were asymptomatic or mildly symptomatic at baseline. PRO indicators that were most significantly indicative of clinical outcomes could provide information to treating physicians and payers on the efficacy and efficiency of healthcare. In the postchemotherapy mCRPC population, these indicators were fatigue intensity, FWB, PWB and prostate cancer-specific signs and symptoms for OS, and pain intensity, FWB and PWB for rPFS. In the chemotherapy-naïve mCRPC patients, PWB was most significantly indicative of rPFS. The relationship between PROs and outcome was detected early: there was a significant association between PROs and improved survival and/or rPFS within 6 months post-treatment. Demonstrating an association between PROs and clinical outcomes early in the treatment course might have beneficial clinical implications, since physicians would be able to consider the clinical significance of their patients’ self-reported perspectives and thus better inform diagnostic and treatment decisions that could enhance utilization of resources and thereby positively affect overall healthcare costs. The 12-month post-treatment sensitivity analyses confirmed that the relationships between PROs and outcomes established at 6 months persisted with longer follow-up. The updated recommendations from the Prostate Cancer Clinical Trials Working Group 3 introduce the ‘no longer clinically benefitting’ reporting metric, which provides actionable recommendations to assist provider-patient decisions regarding treatment discontinuation or change based on therapeutic objectives such as QoL, PROs or survival [18]. To this end, PRO data are increasingly important as healthcare systems across the world move toward a more value-based care approach to patient management [19]. This analysis has important limitations. Clinical trial recruitment is subject to selection bias. Therefore, our study sample may not be representative of all patients with mCRPC. Moreover, there were very few non-Caucasian patients enrolled in these studies (<10%) so the validity of these results in minority populations requires further study. The exploratory nature of these analyses would benefit from replication in subsequent research with a new sample. Finally, although caregiver-reported outcomes were not obtained, they may further serve to inform future diagnostic and treatment decision-making. Conclusions This study is the first to demonstrate the relationship between changes in PROs and clinical outcomes in patients with mCRPC. The results demonstrate that not only are PROs useful in describing patient-relevant outcomes in clinical trials, they hold promise for complementing traditional clinical practice methods for monitoring patients with mCRPC throughout the course of their disease. Acknowledgements Writing assistance was provided by Lashon Pringle, PhD, and Ann Tighe, PhD, of PAREXEL and was funded by Janssen Global Services, LLC. Funding Janssen Research & Development (no grant number applies). The sponsor played a role in the design and conduct of the study; in the collection, management, analysis, and interpretation of data; and in the preparation, review, and approval of the manuscript. Disclosure DC is a consultant to Abbvie, Astellas, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Inc, Evidera, GlaxoSmithKline, Helsinn, Ipsen, Janssen Research & Development and Novartis, and is the president of FACIT.org. ST and TL are employees of Janssen Global Services and hold stock in Johnson & Johnson. KJ and AM were employees of Janssen Global Services and held stock in Johnson & Johnson at the time of the analysis. KFH has served as a consultant to Janssen Global Services. NDS has received research funding from and has served as a consultant to Astellas Pharma, Bayer, Dendreon, Ferring Pharmaceuticals, Janssen Research & Development, Medivation and Sanofi. References 1 Clark MJ, Harris N, Griebsch I et al.   Patient-reported outcome labeling claims and measurement approach for metastatic castration-resistant prostate cancer treatments in the United States and European Union. Health Qual Life Outcomes  2014; 12( 1): 104. Google Scholar CrossRef Search ADS PubMed  2 Diels J, Hamberg P, Ford D et al.   Mapping FACT-P to EQ-5D in a large cross-sectional study of metastatic castration-resistant prostate cancer patients. Qual Life Res  2015; 24( 3): 591– 598. Google Scholar CrossRef Search ADS PubMed  3 Gotay CC, Kawamoto CT, Bottomley A, Efficace F. The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol  2008; 26: 1355– 1363. Google Scholar CrossRef Search ADS PubMed  4 Calvert M, Blazeby J, Altman DG et al.   Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA  2013; 309( 8): 814– 822. Google Scholar CrossRef Search ADS PubMed  5 Basch E, Deal AM, Kris MG et al.   Symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial. J Clin Oncol  2016; 34: 557– 565. Google Scholar CrossRef Search ADS PubMed  6 Basch E, Autio K, Ryan CJ et al.   Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. Lancet Oncol  2013; 14( 12): 1193– 1199. Google Scholar CrossRef Search ADS PubMed  7 Fizazi K, Scher HI, Miller K et al.   Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol  2014; 15( 10): 1147– 1156. Google Scholar CrossRef Search ADS PubMed  8 Loriot Y, Miller K, Sternberg CN et al.   Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol  2015; 16( 5): 509– 521. Google Scholar CrossRef Search ADS PubMed  9 Mehra M, Wu Y, Dhawan R. Healthcare resource use in advanced prostate cancer patients treated with docetaxel. J Med Econ  2012; 15( 5): 836– 843. Google Scholar CrossRef Search ADS PubMed  10 Fizazi K, Scher HI, Molina A et al.   Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol  2012; 13( 10): 983– 992. Google Scholar CrossRef Search ADS PubMed  11 Ryan CJ, Smith MR, Fizazi K et al.   Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol  2015; 16( 2): 152– 160. Google Scholar CrossRef Search ADS PubMed  12 Chi KN, Kheoh T, Ryan CJ et al.   A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. Ann Oncol  2016; 27( 3): 454– 460. Google Scholar CrossRef Search ADS PubMed  13 Ryan CJ, Kheoh T, Li J et al.   Prognostic index model for progression-free survival in chemotherapy-naive metastatic castration-resistant prostate cancer treated with abiraterone acetate plus prednisone. Clin Genitourin Cancer  2017 July 25 [epub ahead of print], doi: 10.1016/j.clgc.2017.07.014. 14 Mendoza TR, Wang XS, Cleeland CS et al.   The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer  1999; 85( 5): 1186– 1196. Google Scholar CrossRef Search ADS PubMed  15 Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore  1994; 23( 2): 129– 138. Google Scholar PubMed  16 Cella D, Nichol MB, Eton D et al.   Estimating clinically meaningful changes for the Functional Assessment of Cancer Therapy–Prostate: results from a clinical trial of patients with metastatic hormone-refractory prostate cancer. Value Health  2009; 12( 1): 124– 129. Google Scholar CrossRef Search ADS PubMed  17 Autio KA, Bennett AV, Jia X et al.   Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure. J Oncol Pract  2013; 9: 223– 229. Google Scholar CrossRef Search ADS PubMed  18 Scher HI, Morris MJ, Stadler WM et al.   Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol  2016; 34: 1402– 1418. Google Scholar CrossRef Search ADS PubMed  19 Schnipper LE, Meropol NJ. Payment for cancer care: time for a new prescription. J Clin Oncol  2014; 32( 36): 4027– 4028. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

Monthly Plan

  • Read unlimited articles
  • Personalized recommendations
  • No expiration
  • Print 20 pages per month
  • 20% off on PDF purchases
  • Organize your research
  • Get updates on your journals and topic searches

$49/month

Start Free Trial

14-day Free Trial

Best Deal — 39% off

Annual Plan

  • All the features of the Professional Plan, but for 39% off!
  • Billed annually
  • No expiration
  • For the normal price of 10 articles elsewhere, you get one full year of unlimited access to articles.

$588

$360/year

billed annually
Start Free Trial

14-day Free Trial