Adding abiraterone to standard hormonal therapy significantly delays disease progression and prolongs survival in metastatic prostate cancer

In a large phase III trial, presented during the plenary session of ASCO 2017, the addition of abiraterone acetate and prednisone to standard hormonal therapy significantly lowered the risk of death by 38% in men with newly diagnosed, high-risk, metastatic prostate cancer (p< 0.0001). Furthermore, abiraterone more than doubled the median time to disease progression, from 14.8 months to 33 months (p< 0.0001). The benefit from early use of abiraterone observed in this study is at least comparable to the benefit from docetaxel chemotherapy, which was observed in prior clinical trials. However, abiraterone is much easier to tolerate, with many patients reporting no side effects at all.

Androgen deprivation therapy (ADT) is active against prostate cancer by preventing testicles from making testosterone. Despite ADT, the adrenal glands and prostate cancer cells continue making small amounts of androgens. Abiraterone stops this production of testosterone throughout the body by blocking an enzyme that converts other hormones to testosterone. Patients with newly diagnosed metastatic hormone-naïve prostate cancer, particularly with high-risk characteristics, have a poor prognosis. ADT plus docetaxel showed improved outcomes in metastatic hormone-naïve prostate cancer, but unfortunately many patients are not eligible for docetaxel and can benefit from alternative therapy.

LATITUDE is a multinational, randomized placebo-controlled phase III clinical trial in men with newly diagnosed, high-risk metastatic prostate cancer who had not previously received ADT. All patients had at least two of three risk factors: a Gleason score of 8 or more, 3 or more bone metastases, or 3 or more visceral metastases. Patients in the study were randomly assigned to receive ADT plus abiraterone and prednisone or ADT plus placebo.

At a median follow up of 30.4 months, men who received abiraterone had a 38% lower risk of death than those who received placebo. The median overall survival had not yet been reached in the abiraterone group and was 34.7 months in the placebo group (HR[95%CI]: 0.62[0.51-0.76]; p< 0.0001). Abiraterone was also associated with a 53% lower risk of cancer progression compared to ADT plus placebo. In fact, the median progression-free survival in the abiraterone arm was 33 months as compared to 14.8 months with ADT plus placebo (HR[95%CI]: 0.47[0.39-0.55]; p< 0.0001). Compared to patients who received ADT and placebo, patients treated with abiraterone in this trial also had a significantly longer time to pain progression (HR[95% CI]: 0.70[0.58-0.83]; p< 0.0001), a longer time to PSA progression (HR[95%]: 0.30[0.26-0.35]; p< 0.0001), a longer time to the first symptomatic skeletal-related event (HR[95%CI]:0.70[0.54-0.92]; p= 0.0086), and a longer time to chemotherapy (HR[95%]: 0.44[0.35-0.56]; p< 0.0001), or subsequent prostate cancer therapy (HR[95%]: 0.42[0.35-0.50]; p< 0.0001).

Several severe side effects were more common with abiraterone acetate and prednisone than with placebo: high blood pressure (in 20% vs. 10% of men), low potassium level (10.4% vs 1.3%), and liver enzyme abnormalities (in 5.5% vs. 1.3% of men). As such, the investigators noted that one needs to be cautious when using abiraterone in men who have an increased risk for heart problems (e.g. diabetics). However, in general, the toxicity profile of ADT in combination with abiraterone and prednisone was manageable.

In summary, early use of abiraterone plus prednisone added to ADT in patients with high-risk metastatic hormone-naïve prostate cancer yielded significantly improved overall and progression-free survival, and also led to significant improvements in all other secondary endpoints as compared to ADT plus placebo. The next step is to see if adding abiraterone on top of docetaxel offers further benefit. A study looking into this matter is currently ongoing in Europe.

Reference

Fizazi K, Tran N, Fein LE, et al. LATITUDE: A phase 3 double-blind, randomized trial of androgen deprivation therapy (ADT) with abiraterone acetate (AA) plus prednisone (P) or placebos (PBOs) in newly diagnosed high-risk metastatic hormone-naïve prostate cancer (mHNPC) patients (pts).Presented at ASCO 2017; Abstract LBA3.