In findings that are being hailed as practice changing, men with metastatic prostate cancer had a near 40% lower risk of death when they were treated with a combination of abiraterone acetate (Zytiga), androgen deprivation therapy, and prednisone or prednisolone, compared with ADT alone.
After a median follow-up of 30.4 months, median overall survival for men with newly diagnosed metastatic, castration-sensitive prostate cancer treated with ADT plus dual placebos was 34.7 months, vs. not reached for men treated with ADT, abiraterone, and prednisone in the. Similarly, in the , men with newly diagnosed locally advanced or metastatic disease who were randomized to ADT with abiraterone and prednisolone had a 37% reduction in their risk for death and a 79% reduction in their risk for treatment failure, compared with men randomized to ADT alone.
The majority of men with metastatic castration-sensitive prostate cancer who are started on androgen deprivation therapy with a luteinizing hormone–releasing hormone (LHRH) analog with or without a first-generation androgen receptor inhibitor will have responses to therapy, but within a median of 1-year most will progress to castration-resistant disease, noted Karim Fizazi, MD, from the Gustave Roussy Cancer Institute at the University of Paris Sud, Villejuif, France, and coinvestigators of the LATITUDE trial.
“Resistance to androgen-deprivation therapy is largely driven by the reactivation of androgen receptor signaling through persistent adrenal androgen production, upregulation of intratumoral testosterone production, modification of the biologic characteristics of androgen receptors, and steroidogenic parallel pathways,” they wrote.
Although ADT and docetaxel is the standard of care for men with metastatic castration-sensitive disease who are eligible for chemotherapy, data from real-world practice suggest that patients with this presentation are older than those enrolled in clinical trials, and may not be able to tolerate the toxicities that occur when docetaxel is added to ADT, they noted.
Abiraterone, in combination with prednisone, has been shown to increase overall survival (OS) in men with metastatic castration-resistant prostate cancer who have not undergone chemotherapy, and among patients who had previously been treated with docetaxel.
The drug is thought to exert its antitumor effects through a combination of androgen receptor antagonism and blockade of steroidogenic enzymes, the investigators wrote.
The LATITUDE trial
LATITUDE investigators from 235 sites in 34 countries in Europe, Asia/Pacific, Latin America and Canada enrolled 1,199 patients with newly diagnosed metastatic castration-sensitive prostate cancer and randomly assigned them to receive either abiraterone and prednisone plus ADT (597 patients), or ADT plus dual placebos (602).
At a planned interim analysis at a median follow-up of 30.4 months, after 406 patients had died, median OS, a co-primary end point, had not been reached among patients in the abiraterone group, compared with 34.7 months for patients assigned to ADT/placebo. This difference translates into a hazard ratio for death of 0.62 (P less than .001).
The median duration of radiographic progression-free survival (PFS), the other primary end point, was 33.0 months among patients treated with abiraterone vs. 14.8 months for those treated with placebo (HR for disease progression or death, 0.47; P less than .001)
Abiraterone was also associated with significantly better outcomes in all secondary endpoints, including time until pain progression, subsequent therapy, initiation of chemotherapy, and prostate-specific antigen (PSA) progression (P less than .001 for each comparison).
The frequency of adverse events leading to treatment discontinuation was 12% for patients in the abiraterone group vs. 10% for those in the placebo group. Rates of grade 3 or 4 hypertension and hypokalemia were higher among patients who received abiraterone.
Based on the trial results, the independent data and safety monitoring committee unanimously recommended unblinding of the trial and allowing patients in the placebo group to receive abiraterone.
The STAMPEDE trial
The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial was designed to test whether adding other therapies to ADT can improve OS in the first-line setting for men with locally advanced or metastatic prostate cancer.
The investigators enrolled 1,917 patients with either newly diagnosed node-positive or metastatic prostate cancer, high-risk locally advanced disease, or relapsed, high-risk disease following radical surgery or radiotherapy.
In all, 95% of patients had newly diagnosed disease; 52% had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative nonmetastatic disease.
After a median follow-up of 40 months, there had been 184 deaths among the 960 patients assigned to received ADT plus abiraterone and prednisolone, compared with 262 deaths among 957 patients assigned to ADT alone. The respective 3-year survival rates were 83% vs. 76%, translating into a HR of 0.63 (P less than .001) favoring abiraterone. The respective hazard ratios for abiraterone in patients with metastatic and nonmetastatic disease were 0.75 and 0.61, respectively.
Failure-free survival (no radiologic, clinical, or prostate-specific antigen progression or prostate cancer death) also favored abiraterone, with a HR of 0.29, compared with ADT alone (P less than .001). The respective hazard ratios for patients with nonmetastatic disease and metastatic disease were 0.21 and 0.31, respectively.
Grade 3 or greater adverse events occurred in 47% of patients on abiraterone, and in 33% of patients treated with ADT alone. There nine deaths on treatment in the abiraterone group, including two cases of pneumonia (one with sepsis), two strokes, and one case each of dyspnea, lower respiratory tract infection, liver failure, pulmonary hemorrhage, and chest infections.
There were three deaths in the ADT alone group, two from myocardial infarctions and one from bronchopneumonia.
LATITUDE was supported by Janssen Research and Development. Dr. Fizazi reported having no relevant conflicts of interest. Multiple coauthors reported personal fees or other support from Janssen and other companies. STAMPEDE was supported by Cancer Research UK, Medical Research Council, Astellas Pharma, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. Lead author Nicholas D. James, PhD, reports receiving support, fees, grants and/or other considerations from Astellas Pharma, Novartis, Pfizer, Clovis Oncology, and Sanofi-Aventis. Multiple coauthors reported similar relationships with various entities.