The addition of abiraterone acetate (Zytiga) plus prednisolone/prednisone to standard androgen-deprivation therapy improves survival in men starting treatment for locally advanced or metastatic, hormone--naive prostate cancer, according to the results of two potentially practice-changing studies presented at the 2017 ASCO Annual Meeting.^1,2

The phase III LATITUDE study, presented at the Plenary Session, showed improved survival when abiraterone plus prednisone was added to androgen-deprivation therapy in newly diagnosed patients with metastatic disease.¹ The STAMPEDE study results—in a much broader patient population that included patients with or without metastatic disease—were presented at an oral abstract session and mirrored those of the LATITUDE trial.²

Taken together, these two phase III studies seem to provide a new treatment paradigm for advanced prostate cancer before it has progressed to castration-resistant disease. Both studies show that abiraterone and prednisolone/prednisone can be safely and effectively added to androgen-deprivation therapy in this setting.

The results of both studies were published online in The New England Journal of Medicine^3,4 to coincide with their presentation at the ASCO Meeting.

Abiraterone acetate plus prednisone added to androgen-deprivation therapy should be considered a new standard of care for newly diagnosed high-risk metastatic prostate cancer.

— Karim Fizazi, MD

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In 2015, docetaxel plus androgen-deprivation therapy was established as a new standard of care for men with metastatic hormone-sensitive prostate cancer, largely based on the -STAMPEDE and CHAARTED trials.^5,6 Abiraterone now joins docetaxel as an option for locally advanced or metastatic disease and may be considered a new standard of care. Both drugs have not been compared head to head in this setting. Adding abiraterone on top of a standard of care of androgen-deprivation therapy plus docetaxel is currently being randomly assessed in the PEACE-1 phase III trial (ClinicalTrials.gov identifier: NCT01957436).

LATITUDE Details

Men with newly diagnosed metastatic prostate cancer account for about 3% of all prostate cancers diagnosed in the United States, and about 60% of all prostate cancers diagnosed in China and India. Castration or androgen-deprivation therapy is the standard of care, and initially, it is nearly 100% effective. However, by the end of the first year of treatment, 50% of men with metastatic disease have progressed to castrate-resistant prostate cancer.

The phase III, placebo-controlled LATITUDE trial was designed to compare the addition of abiraterone plus prednisone to androgen-deprivation therapy vs androgen-deprivation therapy alone in 1,199 men with newly diagnosed, high-risk, hormone-sensitive, metastatic prostate cancer who had not previously received hormone therapy. For patients to be included in the trial, high risk was defined as at least two of the following three risk factors: Gleason score of 8 or more, three or more bone metastases, or measurable visceral metastasis.

LATITUDE Results

At the first preplanned interim analysis, with a median follow-up of 30.4 months, the primary endpoint of overall survival was met. Men who received abiraterone plus prednisone in addition to androgen-deprivation therapy had a 38% lower risk of death than those who received androgen-deprivation therapy plus placebo. The median overall survival had not yet been reached in the abiraterone group and was 34.7 months in the placebo group (P < .0001). At 3 years, 66% of men in the abiraterone group were alive vs 49% of control patients.

Abiraterone was associated with a 53% reduced risk of cancer progression compared with androgen-deprivation therapy plus placebo, delaying disease progression by a median of 18.2 months. The median radiographic progression-free survival was 33 months in the abiraterone group vs 14.8 months in the control group (P < .0001). All secondary endpoints favored abiraterone as well.

“Abiraterone acetate plus prednisone added to androgen-deprivation therapy should be considered a new standard of care for men with newly diagnosed high-risk metastatic prostate cancer,” stated lead author Karim Fizazi, MD, of Gustave Roussy University Paris-Sud, Paris.

More patients in the control arm received subsequent life-prolonging therapy (52%) than those who received abiraterone (40%). Dr. Fizazi noted that this finding suggests -abiraterone’s survival benefit is related to the study drug and not the treatments used after disease progression.

Safety of the abiraterone plus prednisone combination was similar to what has been previously reported, with an excess in grade 4 hypertension with androgen-deprivation therapy alone (20% vs 10%), hypokalemia (10.8% vs 1.2%), and elevated alanine transferase (5.3% vs 1%). Treatment discontinuation due to adverse events was reported in 12% of the abiraterone group and 10% of the control group. Due to an excess in cardiovascular events with abiraterone, Dr. Fizazi urged caution when considering this agent in men with cardiac risk factors.

STAMPEDE Details

The STAMPEDE trial also found a survival benefit with the addition of abiraterone plus prednisolone to androgen-deprivation therapy vs androgen-deprivation therapy alone in men with high-risk locally advanced or metastatic prostate cancer newly diagnosed or relapsed after prostatectomy or radiation therapy who were starting long-term androgen-deprivation therapy.²

This [abiraterone plus androgen-deprivation therapy] is one of the biggest game-changers in prostate cancer.

— Nicholas James, MBBS, PhD

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“Abiraterone acetate prolongs survival after relapsing on first-line therapy, and this is a slightly different setting, with a broader spectrum of patients than enrolled in LATITUDE,” explained lead author Nicholas James, MBBS, PhD, of Queen Elizabeth Hospital, Birmingham, UK.

STAMPEDE is the largest randomized clinical trial of treatments for prostate cancer, testing multiple different treatments simultaneously. “Using this novel multiarm, multistage design, more patients get novel therapies, and we get quicker more economical answers to multiple questions,” Prof. James explained. “This is the sixth combination we tested in this trial and the second agent to demonstrate a substantial survival advantage in this population in the study.”⁵

The STAMPEDE arms reported at this meeting randomized 1,917 men in a 1:1 ratio to receive the standard of care (androgen-deprivation therapy with or without radiation therapy) vs the standard of care plus abiraterone acetate at 1,000 mg plus prednisolone at 5 mg once daily.

The primary endpoint was death from any cause. The median follow-up was 40 months.

STAMPEDE Results

“We found a highly positive result, with a 37% relative improvement in survival [P = .00000115], with 83% alive in the abiraterone arm at 3 years vs 76% in the control arm. The projection is that in the experimental arm, median overall survival will increase from 3.5 years with androgen-deprivation therapy to 6.5 years with abiraterone. This is one of the biggest game-changers in prostate cancer,” Prof. James said.

Failure-free survival was significantly improved by a relative 71% with abiraterone (P = .377 × 10^-61), with 75% of the abiraterone arm free of failure at 3 years vs 45% of the control arm (P = .377 10^–61).

“Abiraterone not only prolonged life, but also lowered the chance of relapse by 70% and reduced the chance of serious bone complications by 50%,” Prof. James said. “Based on the magnitude of clinical benefit, we believe that the upfront care for patients newly diagnosed with advanced prostate cancer should change [to include abiraterone],” he stated.

Abiraterone achieved a highly significant 54% reduction in symptomatic skeletal-related events post relapse. 

Severe side effects (Common Terminology Criteria for Adverse Events [CTCAE] version 4, grade 3–5) were more common in the abiraterone group, occurring in 47% compared with 33% of patients in the standard-of-care arm. The main side effects that were more frequent with abiraterone included hypertension, cardiovascular events, and elevated liver enzymes and were similar to those seen in the relapsed prostate cancer setting.

In a preplanned subgroup analysis of overall survival by metastatic status, the results clearly favored abiraterone on the Forest plot for both metastatic and nonmetastatic disease. Due to fewer deaths in the nonmetastatic setting, the confidence intervals are broader, but statistical tests found no evidence of heterogeneity of effect. Hence the survival benefit applies to both metastatic and nonmetastatic patients. 

STAMPEDE, which continues to recruit new men, has a multi-stage, multi-arm design that allows several treatments to be assessed against a single control arm and for new treatments to be added to the trial as it progresses. Prof. Mahesh Parmar, Director of the Medical Research Council Clinical Trials Unit at University College London, said, “This innovative design allows us to achieve answers to questions decades before the more traditional sequential two-arm trial approach to testing new treatments.” 

The STAMPEDE investigators will report results from at least four more randomized comparisons at future conferences. ■

DISCLOSURE: Dr. Fizazi is on the advisory board for and has received honorarium from Janssen. Dr. James has received unrestricted grants from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi-Aventis. Dr. Pal reported no conflicts of interest.

REFERENCES

1. Fizazi K, et al: LATITUDE: A phase III double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer. 2017 ASCO Annual Meeting. Abstract LBA3. Presented June 4, 2017.

2. James ND, et al: Adding abiraterone for men with high-risk prostate cancer starting long-term androgen deprivation therapy: Survival results from STAMPEDE. 2017 ASCO Annual Meeting. Abstract LBA5003. Presented June 3, 2017.

3. Fizazi K, et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. June 4, 2017 (early release online).

4. James ND, et al: Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. June 3, 2017 (early release online).

5. James ND, et al: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE). Lancet 387:1163-1177, 2016.

6. Sweeney CJ, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015.