Nicholas James, BSc, MBBS, PhD
Earlier intervention with abiraterone acetate (Zytiga) lowered the risk of death by nearly 40% for men with high-risk advanced or metastatic prostate cancer who were newly diagnosed or had not yet received hormone therapy in findings from 2 clinical trials presented at the 2017 ASCO Annual Meeting.
Experts said results from the LATITUDE and STAMPEDE trials would immediately change clinical practice.
Results from the phase III LATITUDE trial demonstrated that the addition of abiraterone plus prednisone to androgen deprivation therapy (ADT) lowered the risk of death by 38%. The combination more than doubled median progression-free survival (PFS) to 33 months compared with 14.8 months for ADT plus placebo in men with newly diagnosed, high-risk metastatic disease (HR, 0.47; 95% CI, 0.39-0.55; P
In the STAMPEDE trial, which consisted of a broader population of high-risk hormone-naïve patients including some participants with nonmetastatic disease, results showed that the addition of abiraterone to standard initial therapy lowered the relative risk of death by 37% and improved the PFS by 71%.2
The 3-year survival rate was 83% with abiraterone plus standard therapy compared with 76% for standard therapy alone.
“It is remarkable to see the similarity in survival benefit across the 2 studies in the metastatic population,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope in Duarte, California, who served as ASCO’s expert commentator during the presscast Saturday where both studies were discussed.
He said the LATITUDE data “should immediately reshape our treatment algorithms for prostate cancer, and abiraterone with conventional hormone therapy should become a new standard of care for men with high-risk metastatic prostate cancer.” He said the STAMPEDE data confirm that approach for metastatic patients but that more study is needed to move abiraterone forward for individuals with nonmetastatic disease.
However, Nicholas James, BSc, MBBS, PhD, lead investigator on the STAMPEDE trial, said abiraterone plus prednisone improves the standard of care for men with hormone-naïve prostate cancer regardless of metastatic disease status.
“Based on the magnitude of clinical benefit, we believe that the upfront care for patients newly diagnosed with advanced prostate cancer should change,” James said in a statement.
The evidence in favor of earlier treatment for patients with advanced or metastatic prostate cancer has been an emerging development in recent years, experts noted at the press conference. In 2014, results from the randomized phase III CHAARTED study involving 790 men demonstrated that the addition of docetaxel to ADT prolonged median overall survival (OS) for men with newly diagnosed metastatic, hormone-sensitive prostate cancer by nearly 14 months compared with ADT alone.3
In 2015, a noteworthy benefit was observed in another part of the STAMPEDE study, which is an ongoing multiarm, multistage randomized clinical trial being conducted in the United Kingdom and Switzerland. The much larger trial, which involved 2962 patients, demonstrated a median OS of approximately 77 months for patients receiving docetaxel plus standard therapy versus 67 months for standard therapy alone in men with newly diagnosed, hormone-naïve advanced prostate cancer.4
Although docetaxel improves outcomes, toxicities associated with the chemotherapy agent are a concern, particularly for older patients who are more likely to develop metastatic prostate cancer, noted Pal. He said abiraterone “provides an important alternative to the use of chemotherapy.”
Abiraterone has been approved by the FDA since 2011 in combination with prednisone for patients with metastatic castration-resistant prostate cancer. The drug, which is orally administered, blocks androgen production by inhibiting CYP17, an enzyme expressed in testicular, adrenal, and prostate tumor tissue.
“The benefit from early use of abiraterone we saw in this study is at least comparable to the benefit from docetaxel chemotherapy which was observed in prior clinical trials, but abiraterone is much easier to tolerate, with many patients reporting no side effects at all,” said Karim Fizazi MD, PhD, lead author of the LATITUDE study, in a statement.
The next step for the research would be to determine whether adding abiraterone to docetaxel and ADT further improves outcomes, said Fizazi, who is head of the department of cancer medicine at Gustave Roussy, University Paris-Sud in Villejuif, France.
LATITUDE Study Findings
The multinational LATITUDE trial enrolled men who had not previously received ADT therapy and had at least 2 of 3 risk factors: Gleason score greater than or equal to 8, measurable visceral metastases, or 3 or more bone lesions. Results presented at the conference were from the first interim analysis involving 1199 patients: 597 in the abiraterone arm and 602 in the control group.
Patients with newly diagnosed metastatic disease live less than 5 years on average, Fizazi said. He said this category includes 3% to 5% of patients in the United States and other Western countries, and rises as high as approximately 60% of newly diagnosed patients in some Asian countries.
The co-primary endpoints for the study were OS and radiographic PFS. Based on results thus far, the International Data Monitoring Committee has unanimously recommended unblinding the study and allowing patients to cross over to the abiraterone arm.
After a median follow-up of 30.4 months, the median overall survival (OS) had not yet been reached (NR) in the abiraterone arm; the median OS in the control group was 34.7 months (HR, 0.62; 95% CI, 0.51-0.76; P
<.0001). The OS rate at 3 years was 66% in the abiraterone group versus 49% with placebo.
The abiraterone-containing regimen also has been shown to significantly improve secondary endpoints compared with the control group in the time to pain progression (NR vs 16.6 months), prostate-specific antigen (PSA) progression (33.2 vs 7.4 months), chemotherapy (NR vs 38.9 months), and subsequent prostate cancer therapy (NR vs 21.6 months). The hazard ratios for those endpoints ranged from 0.30 for PSA progression to 0.70 for pain progression in favor of the abiraterone arm, with P <.0001. The time to symptomatic skeletal-related events was not reached in both arms.
In terms of toxicities, the abiraterone-containing regimen resulted in higher rates of grade 3/4 adverse events compared with the control arm including hypertension (20.3% vs 10.0%); hypokalemia (10.4% vs 1.3%); elevated alanine aminotransferase (5.5% vs 1.3%), and elevated aspartate aminotransferase (4.4% vs 1.5%).
“We need to be cautious when using abiraterone in men who have an increased risk for heart problems, such as those with diabetes,” said Fizazi.
STAMPEDE Trial Results
The STAMPEDE trial is the largest study of first-line abiraterone ever conducted in patients with locally advanced or metastatic prostate therapy. In all, 1917 patients were randomized 1:1 to receive either abiraterone at 1000 mg daily plus prednisone at 5 mg daily plus standard of care (SOC) versus SOC alone. SOC consisted of ADT for at least 2 years with radiotherapy required for participants with N0M0 disease and encouraged for those with stage N+M0.
Treatment duration depended on stage and intent to administer radiotherapy: patients not receiving radiotherapy or with M1 disease were eligible to continue treatment until radiological, clinical, or prostate-specific antigen (PSA) progression. Other patients continued therapy at least 2 years or until progression.
The median age of participants was 67 years (range, 39-85 years); 52% had prostate cancer that had spread, of whom 88% had disease that spread to the bone; and 95% were newly diagnosed.
At a median follow up of 40 months, 184 deaths had occurred in the abiraterone group and 262 deaths in the standard therapy arm. The median adjusted HR for the median OS was 0.63 (95% CI, 0.52-0.76; P
= .0000012). Abiraterone-containing therapy also markedly improved skeletal-related outcomes with a 55% reduction in the time for such problems to develop (HR, O.45; 95% CI, 0.36-0.38).
Although most adverse events (AEs) were similar between the 2 groups, researchers reported that serious AEs occurred more frequently among participants who received abiraterone, with 41% of patients reporting grade 3/4 AEs compared with 29% in the standard therapy group.
As with the LATITUDE trial, the main AEs occurring more frequently with abiraterone were cardiovascular problems such as high blood pressure; there were also more liver problems. There were 2 treatment-related deaths in the abiraterone group and in the standard therapy group, researchers reported.
- Fizaxi K, Tran N, Fein LE, et al; the LATITUDE investigators. 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). J Clin Oncol. 2017;35 (suppl; abstr LBA3).
- James ND, DeBono JS, Spears MR, et al. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE (NCT00268476). J Clin Oncol. 2017;35 (suppl; abstr LBA5003).
- Sweeney C, Chen Y-H, Carducci MA, et al. Impact on OS with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: an ECOG-led phase III randomized trial. J Clin Oncol. 2014;32 (5 suppl; abstr LBA2).
- James ND, Sydes, MR, Mason, MD, et al. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: First overall survival results from STAMPEDE. J Clin Oncol. 2015;33 (suppl; abstr 5001).