Androgen Deprivation, With or Without Radiotherapy, New Standard of Care in High-Risk Prostate Cancer

A CLINICALLY AND STATISTICALLY

significant effect on overall survival (OS) and failure-free survival (FFS) from the addition of abiraterone at the start of androgen deprivation therapy (ADT) in men with high-risk prostate cancer was reported as a late-breaking abstract at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting. Abiraterone has shown a survival advantage in men with castration-refractory prostate cancer. The investigators queried whether abiraterone would exert an effect earlier in the disease.

Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE), a randomized controlled trial that employs a multi-arm, multistage platform design, was initiated in 2005 and will complete data collection for analysis of the primary outcome measures in September 2017. Patients with high-risk, locally advanced, or metastatic prostate cancer starting long-term androgen deprivation therapy are being recruited. The first comparative survival data were reported at ASCO.

The primary outcome measures include the safety of ADT alone versus ADT in combination with enzalutamide and abiraterone and/or radiotherapy to the prostate (and previously celecoxib, zoledronic acid, docetaxel, and abiraterone alone) in patients with locally advanced or metastatic prostate cancer, FFS, and OS.¹ The study will determine which treatment is cost-effective. More than 5000 patients have participated and answers have become available over 7 to 12 years.¹

The standard of care was ADT for ≥2 years. Radiotherapy was mandated for men with N0M0 disease and encouraged for those with N+M0. Stratified randomization allocated patients 1:1 to standard of care or standard of care with abiraterone (1000 mg) and prednisolone (5 mg) daily. Treatment duration depended on stage and intent to administer radical radiotherapy. In patients not receiving radiotherapy or with M1 disease, treatment continued until progression as determined by prostate specific antigen (PSA) level, imaging, and clinical determination. Otherwise, treatment continued until the earlier of 2 years or all types of progression.

Among the 1917 patients, randomized from 2011 to 2014, the median age was 67 years, 52% were metastatic, 20% had N+/XM0 disease, 28% had N0M0 disease, and the median PSA was 53 ng/mL. Over 40-months of median follow-up, 262 deaths occurred in the control arm (82% from prostate cancer).

For standard of care plus abiraterone versus standard of care alone, the adjusted hazard ratio (HR) was 0.63 (95% CI, 0.52-0.76; P = .115 10^-7; 184 deaths), with 3-year OS improved from 76% to 83%. A total of 535 FFS events occurred in the control arm. The adjusted HR was 0.29 (95% CI, 0.25 - 0.34; P = .377 10^-63; 248 FFS events) for standard of care plus abiraterone versus standard of care alone.

Grade 3 adverse events (AEs) were noted in 29% and 3% of patients who received standard of care alone versus standard of care plus abiraterone, respectively; grade 4 AEs in 41% and 5% of patients, respectively; and grade 5 AEs in 3% and 9% of patients, respectively (1% and 2%, respectively, related to the drug).

The researchers concluded that the addition of abiraterone at the start of ADT resulted in a clinically and statistically significant effect on OS and FFS, with a manageable increase in toxicity. ADT with or without radiotherapy has been shown to be a new standard of care in men with high-risk prostate cancer.

Abiraterone acetate is a selective, irreversible inhibitor of CYP17. Androgen depletion with CYP17 inhibition plus ADT is more effective than surgical castration or gonadotropin releasing hormone analogues alone.²REFERENCES

1. STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: a multistage multi-arm randomised controlled trial (STAMPEDE). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/ NCT00268476. Updated July 24, 2014. Accessed June 30, 2017.

2. James ND, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy [published online June 3, 2017]. N Engl J Med. 2017. doi: 10.1056/NEJMoa1702900.

Download PDF: Androgen Deprivation, With or Without Radiotherapy, New Standard of Care in High-Risk Prostate Cancer