ZYTIGA® data on pain and function

Additional data from pre-specified interim analyses of COU-AA-302, a Phase III, randomised, placebo-controlled study, suggested ZYTIGA® (abiraterone acetate) plus prednisone, compared to placebo plus prednisone, delayed pain progression and functional decline in asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients whose disease progressed after androgen deprivation therapy and anti-androgens.(1)

Additional data from COU-AA-302 suggest that the assessment of radiographic progression-free survival (rPFS), adapted from Prostate Cancer Working Group 2 (PCWG2) consensus criteria, was highly consistent between investigators and independent blinded radiologists and was positively associated with overall survival (OS).(2) The results were presented today at the ESMO 2012 Congress (European Society for Medical Oncology) in Vienna, Austria.

Safety and efficacy findings from COU-AA-302 were the basis of recent filings with health authorities around the world to extend the use of ZYTIGA® administered with prednisone to include the treatment of patients with mCRPC who are asymptomatic or mildly symptomatic and whose disease progressed after androgen deprivation therapy and anti-androgens.

“We understand that managing pain and maintaining function are of critical importance to prescribing physicians and patients, which is why we included and analysed these endpoints,” said Michael L. Meyers, MD, PhD, Vice President, Compound Development Team Leader, ZYTIGA®. “These data, from a second pivotal Phase III study, add to the growing body of knowledge about ZYTIGA® in this patient population where significant unmet medical needs remain.”

Study COU-AA-302 is a Phase III, randomised, double-blind, placebo-controlled, international study that included 1,088 men with mCRPC who had not received prior chemotherapy, and who were randomised to receive ZYTIGA® 1,000 milligrams (mg) administered orally once daily plus prednisone 5 mg administered twice daily (n=546; ZYTIGA arm) or placebo plus prednisone 5 mg administered twice daily (n=542; control arm). The co-primary endpoints of the study are rPFS and OS; these data were presented earlier in 2012. Functional status and pain progression were secondary endpoints.

The patients reported their pain and functional status at baseline and on the first day of pre-specified treatment cycles over 13.8 months and 8.3 months in the two arms, respectively, using standard, validated instruments: the Brief Pain Inventory – Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy – Prostate Cancer (FACT-P). Both the BPI-SF and FACT-P questionnaires are used to assess pain and health-related quality of life in men with prostate cancer.(1)

Patients in the ZYTIGA® arm reported statistically significant delays in most measures of pain progression and functional decline compared to those in the control arm, and the median number of months to reach pre-defined degrees of worsening were greater (more delayed) in the ZYTIGA® arm versus the control arm, respectively:(1)

Average pain progression: 26.7 versus 18.4 months (HR=0.817; 95% CI: [0.668, 0.999]; p=0.049)

Worst pain intensity progression: 14.8 versus 12.0 months (HR=0.777; 95% CI: [0.607, 0.995]; p=0.045)

Progression of pain interference with daily function: 10.3 versus 7.4 months (HR=0.792; 95% CI: [0.674, 0.931]; p = 0.005)

Median time to opiate use for cancer pain: not reached in ZYTIGA® arm versus 23.7 months (HR=0.817; 95% CI: [0.668, 0.999]; p=0.0001)

• FACT-G score (general function status): 16.6 versus 11.1 (HR=0.76; 95% CI: [0.63, 0.91]; p=0.002)
• FACT-P total score: 12.7 versus 8.3 months (HR=0.778; 95% CI: [0.659, 0.918]; p=0.003)
• Physical well-being: 14.8 versus 11.1 months (HR=0.76; 95% CI: [0.64, 0.90]; p=0.002)
• Emotional well-being: 22.1 versus 14.2 months (HR= 0.71; 95% CI: [0.59, 0.87]; p=0.001)
• Functional well-being: 13.3 versus 8.4 months (HR=0.76; 95% CI: [0.64, 0.90]; p=0.001)
• Prostate cancer subscale score: 11.1 versus 5.8 months (HR=0.70; 95% CI: [0.60, 0.83]; p<0.001)
• Differences for the two treatment groups of worst pain intensity (26.7 versus 19.4 months; HR=0.845; 95% CI: [0.688, 1.038]; p=0.109) and social/family well-being (18.4 versus 16.6 months; HR=0.94; 95% CI: [0.78, 1.14]; p=0.528) were not statistically significant.

Additional data from COU-AA-302 allowed investigators to examine the correlation between rPFS and OS. The investigators found a positive association of rPFS with OS (correlation coefficient r = +0.71, possible range -1 to +1). Furthermore, the findings suggested that the assessment of rPFS was highly consistent between investigators and independent blinded radiologists, suggesting that this novel endpoint adapted from PCWG2 criteria is reliable and reproducible.(2)

“The association between rPFS and OS provides preliminary support for use of radiographic progression-free survival as an intermediate marker of overall survival, and as a primary/co-primary endpoint in Phase III mCRPC studies,” said Charles J. Ryan, MD, lead investigator of the study and Associate Professor of Clinical Medicine at the UCSF Helen Diller Family Comprehensive Cancer Center.(3)

Previously reported safety findings showed that patients in the ZYTIGA® arm of the study experienced more grade 3 and grade 4 adverse events than those in the control arm, including cardiac disorders (6% versus 3%) and hypertension (4% versus 3%), as well as increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (5.4% versus 0.8% and 3.0% versus 0.9%, respectively). Fatigue was the most common adverse event observed in the study.

1. ESMO abstract 8950 – Basch et al. THE IMPACT OF ABIRATERONE ACETATE (AA) THERAPY ON PATIENT-REPORTED PAIN AND FUNCTIONAL STATUS IN CHEMOTHERAPY-NAIVE PATIENTS WITH PROGRESSIVE, METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)
2. ESMO abstract 8940 – Ryan et al. ASSOCIATION OF RADIOGRAPHIC PROGRESSION-FREE SURVIVAL (RPFS) ADAPTED FROM PROSTATE CANCER WORKING GROUP 2 (PCWG2) CONSENSUS CRITERIA (APCWG2) WITH OVERALL SURVIVAL (OS) IN PATIENTS (PTS) WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC).
3. ZYTIGA® summary of product characteristics 2011.