ArticlesEffect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial
Introduction
Symptomatic bone metastases are a characteristic feature of progressing metastatic castration-resistant prostate cancer and account for much of the morbidity in patients with this illness.1, 2 The risk of mortality increases with the spread of cancer to bone, especially when accompanied by skeletal-related events; time to skeletal-related events is an important prognostic marker in metastatic castration-resistant prostate cancer.3 The volume of bone metastases and associated pain correlate with poor survival.4, 5, 6 These findings validate efforts to develop better methods for detection, monitoring, treatment, and prevention of bone metastases in prostate cancer.7, 8, 9, 10, 11, 12
Several lines of experimental and clinical evidence support the hypothesis that molecular pathways central to bone development and function are usurped by prostate cancer during disease progression and treatment resistance.13, 14 Androgen receptor signalling networks are key drivers of progression in prostate cancer,15 and emerging data suggest that the shift from endocrine-driven to intracrine-driven (ie, paracrine and autocrine) prostate cancer under the selective pressure of castration is crucial.1, 14, 16, 17 The development of a dominant paracrine-signalling progression pathway within bone, part of a broader network of interacting progression pathways, might account for the unique phenotype of metastatic castration-resistant prostate cancer.1
Abiraterone acetate is a selective androgen biosynthesis inhibitor that blocks CYP17 (a key enzyme in testosterone and dihydrotestosterone production) and therefore shuts down androgen production in the adrenals and testes and prostate cancer cells. The results of a 2012 study18 suggest that the expression of androgen receptors and CYP17 is predictive of abiraterone acetate's treatment benefit in patients with castration-resistant prostate cancer who have bone metastases.
We reasoned that a drug that has been previously shown to potently inhibit the signalling pathways implicated in the progression of bone metastases in prostate cancer might also positively affect bone-associated symptoms. To establish whether CYP17 inhibition with abiraterone acetate can improve pain and manifestations of bone metastases in metastatic castration-resistant prostate cancer after treatment with docetaxel, we prospectively measured and analysed patient-reported pain and the occurrence of skeletal-related events from the COU-AA-301 trial.16
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Study design and patients
COU-AA-301 was a randomised, double-blind, placebo-controlled phase 3 study at 147 sites in 13 countries in patients with metastatic castration-resistant prostate cancer who had been treated unsuccessfully with one or two lines of chemotherapy (one of which was docetaxel based).16 Patients were required to have a serum testosterone concentration of 50 ng/dL or less (≤2·0 nmol/L) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and to meet predefined
Results
Results of the COU-AA-301 trial24 have been reported previously. 797 patients were randomly assigned to abiraterone acetate plus prednisone and 398 to placebo plus prednisone; these patients comprised the intention-to-treat population. Demographics were similar across treatment groups,16 and median age was 69 years in both groups (table 1).
Table 2 lists patients' baseline factors on the basis of the presence or absence of baseline pain. 1068 of 1195 (89·4%) patients had bone metastases.16 Mean
Discussion
In this study we showed that abiraterone acetate plus prednisone favourably affects measures of bone-related symptoms (patient-reported pain palliation, delay in pain progression, and delayed time to skeletal-related events) in metastatic castration-resistant prostate cancer compared with prednisone alone (panel 2). Pain palliation also occurred faster with abiraterone acetate and prednisone than with placebo and prednisone. We interpret these findings to be supportive of the hypothesis that
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These authors contributed equally