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Reference – LATITUDE trial (N Engl J Med 2017 Jun early online) (level 1 [likely reliable] evidence)
- The addition of abiraterone to prednisone in men treated for castration-resistant prostate cancer has been shown to improve survival. The effect of the addition of abiraterone plus prednisone to androgen-deprivation therapy (ADT) in men with hormone-sensitive metastatic prostate cancer is unknown.
- The LATITUDE trial evaluated 1,199 men (median age 68 years) with newly diagnosed high-risk metastatic, hormone-sensitive prostate cancer who had started ADT < 3 months previously. The men were randomized to abiraterone acetate 1,000 mg orally once daily plus prednisone 5 mg orally once daily vs. dual placebo.
- Addition of abiraterone plus prednisone to ADT increased the likelihood of 3-year overall survival (in 66% with abiraterone plus prednisone vs. 49% with placebo, p < 0.001, NNT 6).
Addition of abiraterone, an androgen biosynthesis inhibitor, has been shown to be associated with improved survival in men with metastatic castration-resistant prostate cancer receiving prednisone who were previously treated with docetaxel (N Engl J Med 2011 May 26;364(21):1995) and who were chemotherapy naïve (Lancet Oncol 2015 Feb;16(2):152). To investigate the efficacy of abiraterone plus prednisone in men with metastatic hormone-sensitive prostate cancer, the recent LATITUDE trial evaluated men with newly diagnosed metastatic prostate cancer who had started ADT < 3 months previously and had ≥ 2 of 3 high-risk factors associated with poor prognosis including ≥ 3 bone lesions, a Gleason score ≥ 8, and measurable visceral metastasis. In this trial, 1,199 men (median age 68 years) were randomized to abiraterone acetate 1,000 mg orally once daily plus prednisone 5 mg orally once daily vs. dual placebo. In men who were not surgically castrated, ongoing ADT was targeted to maintain serum testosterone < 50 ng/dL (1.7 nmol/L). The trial was terminated at a median follow-up of 30.4 months after the first interim analysis indicated increased efficacy for abiraterone plus prednisone according to a prespecified stopping rule. About 53% of patients with abiraterone plus prednisone and 78% with placebo discontinued treatment and were eligible for subsequent therapy. Overall survival at 3 years was 66% with abiraterone plus prednisone vs. 49% with placebo (p < 0.001, NNT 6), and abiraterone plus prednisone was associated with a reduced risk of death during the follow-up (hazard ratio 0.62, 95% CI 0.51-0.76). Abiraterone plus prednisone was also associated with favorable cancer-specific outcomes: the median time to radiographic progression-free survival was 33 months vs. 14.8 months (p < 0.001), and the median time to prostate-specific antigen progression was 33.2 months vs. 7.4 months (p < 0.001). In addition, the median time to pain progression, subsequent prostate cancer therapy, and skeletal events were all prolonged with abiraterone plus prednisone compared to placebo. Grade 3 or 4 adverse events were reported in 63% with abiraterone plus prednisone and in 48% with placebo, including hypertension in 20% vs. 10%, hypokalemia in about 10% vs. 1%, elevated alanine transaminase in 5.5% vs. 1.3%, and elevated aspartate aminotransferase in 4.4% vs. 1.5% (statistical comparisons not reported). In the LATITUDE trial, the addition of abiraterone plus prednisone to ADT led to improved survival as well as cancer-specific outcomes in men with newly diagnosed metastatic hormone-sensitive prostate cancer. Consistent results for prolonged survival were found in the open-label STAMPEDE trial investigating the addition of abiraterone plus prednisolone to newly started ADT (N Engl J Med 2017 Jun 3 early online). The 1,917 men in the STAMPEDE trial were treated for either metastatic (in 52%) or high-risk locally advanced prostate cancer and were followed for a median of 40 months. The adverse effects reported in these trials suggest that careful monitoring of patients for hypertension, hypokalemia, and liver enzyme elevations may be necessary. Due to possible interactions between abiraterone acetate and other medications that may influence cytochrome P450 enzyme activities (FDA DailyMed 2017 June 9), patients should be assessed for other medication use. From the ongoing PEACE-1 trial, findings whether the addition of docetaxel to abiraterone plus prednisone further improves survival in patients with hormone-sensitive metastatic disease should eventually become available. In summary, the results of the LATITUDE and STAMPEDE trials indicate that the early addition of abiraterone acetate plus prednisone to ADT is beneficial for survival in men with hormone-sensitive high-risk locally advanced or metastatic prostate cancer.
For more information, see the Management of hormone-sensitive metastatic prostate cancer topic in DynaMed plus. DynaMed users click here.