Some newly diagnosed patients with prostate cancer reduced their risk of death with earlier use of Zytiga, according to two trials presented at the ASCO Annual Meeting.
With earlier intervention with Zytiga (abiraterone acetate) the risk of death was decreased by nearly 40 percent for men with high-risk advanced or metastatic prostate cancer who were newly diagnosed and now not yet received hormone therapy, according to findings of two clinical trials presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.
Experts said results from the LATITUDE and STAMPEDE trials would immediately change clinical practice.
Results from the phase 3 LATITUDE trial demonstrated that the addition of Zytiga plus prednisone to androgen deprivation therapy (ADT) lowered the risk of death by 38 percent. 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.
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 Zytiga to standard initial therapy lowered the relative risk of death by 37 percent and improved the PFS by 71 percent. The three-year survival rate was 83 percent with Zytiga plus standard therapy compared with 76 percent for standard therapy alone.
“It is remarkable to see the similarity in survival benefit across the two studies in the metastatic population,” said Sumanta Kumar Pal, M.D., 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 Zytiga 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 Zytiga forward for individuals with nonmetastatic disease.
However, Nicholas James, BSc, MBBS, Ph.D., lead investigator on the STAMPEDE trial, said Zytiga 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 3 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.
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.
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 Zytiga “provides an important alternative to the use of chemotherapy.”
Zytiga 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 Zytiga we saw in this study is at least comparable to the benefit from docetaxel chemotherapy which was observed in prior clinical trials, but Zytiga is much easier to tolerate, with many patients reporting no side effects at all,” said Karim Fizazi M.D., Ph.D., lead author of the LATITUDE study, in a statement.
The next step for the research would be to determine whether adding Zytiga 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 two of three risk factors: Gleason score greater than or equal to 8, measurable visceral metastases or three or more bone lesions. Results presented at the conference were from the first interim analysis involving 1,199 patients: 597 in the Zytiga arm and 602 in the control group.
Patients with newly diagnosed metastatic disease live less than five years on average, Fizazi said. He said this category includes 3 percent to 5 percent of patients in the United States and other Western countries, and rises as high as approximately 60 percent 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 Zytiga arm.
After a median follow-up of 30.4 months, the median overall survival (OS) had not yet been reached (NR) in the Zytiga arm; the median OS in the control group was 34.7 months. The OS rate at three years was 66 percent in the Zytiga group versus 49 percent with placebo.
The Zytiga -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).
In terms of toxicities, the Zytiga -containing regimen resulted in higher rates of grade 3/4 adverse events compared with the control arm including hypertension (20.3 percent vs 10.0 percent); hypokalemia (10.4 percent vs 1.3 percent); elevated alanine aminotransferase (5.5 percent vs 1.3 percent), and elevated aspartate aminotransferase (4.4 percent vs 1.5 percent).
“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 Zytiga ever conducted in patients with locally advanced or metastatic prostate therapy. In all, 1,917 patients were randomized in a 1-1 ratio to receive either Zytiga 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 two 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 two years or until progression.
The median age of participants was 67 years (range, 39-85 years); 52 percent had prostate cancer that had spread, of whom 88 percent had disease that spread to the bone; and 95 percent were newly diagnosed.
At a median follow up of 40 months, 184 deaths had occurred in the Zytiga group and 262 deaths in the standard therapy arm. The median adjusted HR for the median OS was 0.63. Zytiga -containing therapy also markedly improved skeletal-related outcomes with a 55 percent reduction in the time for such problems to develop.
Although most adverse events (AEs) were similar between the two groups, researchers reported that serious AEs occurred more frequently among participants who received Zytiga, with 41 percent of patients reporting grade 3/4 AEs compared with 29 percent in the standard therapy group.
As with the LATITUDE trial, the main AEs occurring more frequently with Zytiga were cardiovascular problems such as high blood pressure; there were also more liver problems. There were two treatment-related deaths in the Zytiga group and in the standard therapy group, researchers reported.