Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

Abstract

BACKGROUND\ud Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.\ud METHODS\ud We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).\ud RESULTS\ud A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events).\ud CONCLUSIONS\ud Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.

Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

“…This has led to advances in antiandrogen therapy, with the successful development of abiraterone and enzalutamide (9)(10)(11)(12)(13). Despite these advances, primary resistance is common and secondary resistance on treatment inevitable in CRPC, in part due to expression of constitutively active AR splice variants that evade current antiandrogen treatment strategies (14,15,(21)(22)(23)(24)(25)(26).…”

“…There is increasing evidence of persistent AR signaling as patients progress to CRPC with rising prostate specific antigen (PSA), increasing steroidogenesis, overexpression of AR co-regulators and the development of AR aberrations (6)(7)(8). The discovery of second generation anti-androgen therapies, such as abiraterone and enzalutamide, that effectively target AR signaling in patients with hormone sensitive disease and CRPC has improved patient outcome (9)(10)(11)(12)(13). However, primary and secondary resistance to both therapies is common and may, in part, be due to the expression of constitutively active AR splice variants of which AR variant 7 (AR-V7) is considered the most significant and best studied (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

The Changing Therapeutic Landscape in Metastatic Prostate Cancer

“…12 In the STAMPEDE trial, 1,917 patients with newly diagnosed locally advanced or high-risk mHSPC were randomized 1:1 to receive either abiraterone acetate (1,000 mg daily) plus prednisone (5 mg daily), plus standard of care (SOC) or SOC alone, defined as the administration of ADT therapy for 2 years or until disease progression. 13 At time of study entry, 95% of patients were newly diagnosed, 52% had metastatic disease, and 88% had disease that had metastasized to bone. At a median follow-up of 40 months, 184 deaths had occurred in the abiraterone arm and 262 deaths in the SOC arm.…”

New research in prostate cancer, ASCO 2017

“…2,3 In addition to the presentations at ASCO, both studies were also simultaneously published in the New England Journal of Medicine. 4,5 In the LATITUDE study, 2,4 the definition of high-risk was at least two of the following three characteristics: Gleason score ≥8, presence of ≥3 lesions on bone scan, and presence of measurable visceral lesion.Patients were randomized to receive ADT + AAP (1000/5 mg QD, n=597) or ADT + placebo (n=602). The treatment arms were well-balanced in terms of baseline characteristics.…”

“…3,5 For inclusion in this study, patients had to be hormone-naïve and be newly diagnosed with metastatic or node-positive disease, or have high-risk locally advanced disease defined as having at least two of the following: stage T3/4, PSA >40 ng/mL, and Gleason score 8-10. Alternatively, patients could be enrolled if they relapsed after previous radical prostatectomy or radiotherapy, and had at least one of the following inclusion criteria: PSA at least 4 ng/mL and rising, with doubling time less than six months; PSA 20 ng/mL or greater, node-positive, or metastatic.…”