LATITUDE Study: Abiraterone Plus Prednisone Might Be Clinically Beneficial in Men with Metastatic Castration-Sensitive Prostate Cancer

Introduction

Newly diagnosed prostate cancer cases initially respond to androgen deprivation therapy (ADT). However, most men progress to castration-resistant prostate cancer (CRPC) within a median of 1 year. Intratumoral androgen synthesis is one of the mechanisms in the emergence of CRPC and hence is a legitimate target for therapy. Abiraterone acetate inhibits cytochrome P-450c17, a critical enzyme in androgen biosynthesis. Evidence has demonstrated the beneficial clinical effects of abiraterone plus prednisone in men with metastatic castration-resistant prostate cancer who have not received chemotherapy and in those who have received previous docetaxel. A combination of abiraterone plus prednisone and ADT have been shown to reduce the tumor burden in newly diagnosed metastatic castration-sensitive prostate cancer men before the emergence of castration resistance. Thus, this trial tests the efficacy and safety of abiraterone plus prednisone along with ADT as a less toxic alternative to chemotherapy.

Aim

To compare the clinical benefits of addition of abiraterone plus prednisone to androgen deprivation therapy with androgen-deprivation therapy alone in men with newly diagnosed metastatic castration-sensitive prostate cancer.

Patient Profile

• Age >18 years
• Prostate cancer diagnosed <3 months before randomization
• High risk metastatic castration-sensitive prostate cancer documented by a positive bone scan or CT or MRI
• Patients with at least 2 or the 3 high risk factors
  • Gleason score of 8 or more
  • At least 3 bone lesions
  • Presence of measurable visceral metastasis

Method

Study Design

Multinational, randomized, double-blind, placebo-controlled phase 3 trial.

Treatment Strategy

• N=1199 randomized in 1:1 ratio
• Treatment group of 597 men, received androgen-deprivation therapy and abiraterone acetate (1000 mg daily, given once daily as four 250 mg tablets) and 5 mg prednisone once daily
• The placebo group of 602 men, received androgen-deprivation therapy and placebos

Endpoints

• Overall survival defined as time from randomization to death from any cause
• Radiographic progression-free survival defined as time from randomization to occurrence of radiographic progression or death from any cause
• Secondary endpoints included time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy and prostate-specific antigen progression and next symptomatic skeletal events

Results

• The first interim analysis was performed after 406 deaths and a median follow-up of 30.4 months
• Treatment group reported 28% of the deaths versus 39% in the placebo group
• Abiraterone group had a significantly higher overall rate of survival of 66% at 3 years as compared to 49% in the placebo group
• Death due to any cause was 28% and 39% respectively in the treatment and placebo groups respectively
• The relative risk of death was 38% lower in the abiraterone group (HR 0.62; p<0.001)
• The median progression-free survival was longer in the treatment group (33 months vs 14.8 months)
• Relative risk of radiographic progression or death was 53% lower in the abiraterone group (HR 0.47; p<0.001)
• The abiraterone group had significantly better outcomes in the secondary endpoints as shown in table 1.

• Abiraterone group had a higher incidence of grade 3 or 4 adverse events (63% vs 48%)
• Rates of grade 3 and grade 4 hypertension were 20% and 0% respectively in the abiraterone group as compared to 10% and 0.2% respectively in the placebo group

• Rates of grade 3 and grade 4 hypokalemia were 10% and 0.8% respectively in the abiraterone group as compared to 1% and 0.2% respectively in the placebo group
• Because of the unequivocal superiority of the abiraterone and ADT combination over the active comparator of ADT only, the independent data and safety monitoring committee unanimously recommended that the trial be unblinded to allow a cross-over among the patients in placebo arm to receive abiraterone.

Conclusion

• Addition of abiraterone plus prednisone to androgen-deprivation therapy led to significantly longer overall survival and longer radiographic progression-free survival as compared to androgen-deprivation therapy alone in men newly diagnosed with metastatic castration-sensitive prostate cancer
• The abiraterone group was associated with higher rates of grade 3 hypertension and hypokalemia, which were medically manageable

N Engl J Med 2017, 377:352-60. Doi: 10.1056/NEJMoa1704174.