Dr. Nicholas D. James presents Abstract 5003.
“Abiraterone acetate plus prednisolone should be part of the standard of care for men starting long-term ADT,” Nicholas D. James, BSc, MBBS, PhD, of Queen Elizabeth Hospital and the University of Birmingham, in the United Kingdom, said. He presented the results of the STAMPEDE trial during the Genitourinary (Prostate) Cancer Oral Abstract Session on June 3.
Approximately 3% to 5% of men diagnosed with prostate cancer have metastasis at diagnosis in Western countries; in some large countries in Asia, however, that incidence can be as high as 60%, Karim Fizazi, MD, PhD, of the Gustave Roussy Cancer Campus and University Paris-Sud, in France, said during an ASCO Press Briefing on June 3. Dr. Fizazi presented results of the LATITUDE trial during the Plenary Session on June 4. Historically, ADT has been the standard of care for patients with hormone-sensitive, locally advanced or metastatic disease, and in the past several years docetaxel has been added to that therapy for patients with high metastatic burden.
The STAMPEDE trial began in 2005 and is the largest randomized clinical trial of treatments for prostate cancer. This ongoing study has a multistage, multi-arm design to allow adaption and addition of new therapies. An abiraterone comparison arm was opened in 2011 and closed January 2014. Enrolled patients included those with high-risk locally advanced or metastatic prostate cancer that was newly diagnosed or relapsed after radical prostatectomy or radiation therapy and who were starting ADT.
Dr. Karim Fizazi presents LBA3.
For the abiraterone comparison arm of STAMPEDE, patients were randomly assigned 1:1 to receive the standard of care of ADT with radiation therapy if eligible (mandated for N0M0 or encouraged for N+M0 disease) or the standard of care plus abiraterone and prednisolone. Of the 1,917 patients enrolled, 957 were assigned to standard of care and 960 to standard of care plus abiraterone acetate and prednisolone.
The groups were well balanced at baseline. Of the patients enrolled, 21% and 1% had a World Health Organization performance status of 1 and 2, respectively. Metastatic disease was present in 52%, and 88% of those patients had bony metastases. Staging was N0M0 in 28% of patients and N+M0 in 20%. Five percent of patients had received previous local therapy.
In the abiraterone group, OS was improved by 37% compared with the standard-of-care group (hazard ratio [HR] 0.63, 95% CI [0.52, 0.76]; p = 0.00000115). There was “no good evidence of heterogeneity by stratification factors,” Dr. James said, including metastatic disease.
Early addition of abiraterone and prednisolone improved OS by 37% and FFS by 71%, and reduced symptomatic skeletal events by 55%, Dr. James said.
The benefit in FFS was pronounced. Time to failure improved by 71% in the abiraterone group (HR 0.29, 95% CI [0.25, 0.34]; p = 0.377x10-61). Dr. James pointed out the unusually small probability value. Again, he said, there was no good evidence for heterogeneity by stratification factors, including metastatic disease.
Regarding safety, the number of grade 3 to 5 adverse events was similar in most categories, although the abiraterone group reported more cardiovascular disorders than the standard-of-care group (10% vs. 4%, respectively) and more hepatic disorders (7% vs. 1%, respectively).
In all patients, skeletal-related events were reduced in the abiraterone treatment group (HR 0.46, 95% CI [0.37, 0.58]; p = 0.0000000000169). Among patients with M1 cancer staging, the difference was even more pronounced, with a 55% reduction in skeletal-related events in the abiraterone treatment group compared with standard of care (HR 0.45, 95% CI [0.36, 0.58]; p value not presented).
Tanya B. Dorff discusses Abstract 5003.
The results presented by Dr. Fizazi during the Plenary Session represented the first planned interim analysis, which because of the positive findings, he said now becomes the final analysis. After a median follow-up of 30.4 months, the OS endpoint was met, with a significant reduction in the risk of death with abiraterone and prednisone. The median OS with ADT and placebo was 34.7 months, but was not yet reached in the abiraterone group (HR 0.62, 95% CI [0.51, 0.76]; p < 0.0001). The OS rate at 3 years was 66% with abiraterone and prednisone, and 49% without.
rPFS improved with abiraterone as well. The median rPFS in the control group was 14.8 months compared with 33.0 months with abiraterone (HR 0.47, 95% CI [0.39, 0.55]; p < 0.0001).
All secondary endpoints of the trial were also met. The addition of abiraterone improved time to PSA progression (HR 0.30, 95% CI [0.26, 0.35]; p < 0.0001); time to pain progression (HR 0.70 [0.58, 0.83]; p < 0.0001); time to next symptomatic skeletal event (HR 0.70, 95% CI [0.54, 0.92]; p = 0.0086); time to chemotherapy (HR 0.44, 95% [0.35, 0.56]; p < 0.0001); and time to subsequent prostate cancer therapy (HR 0.42, 95% CI [0.35, 0.50]; p < 0.0001).
Notably, more patients in the control arm received subsequent life-prolonging therapy (52%) than in the abiraterone arm (40%). This suggests that the survival benefit seen with abiraterone plus prednisone is related to the study drug rather than to drugs used after progression.
“The safety profile of ADT with the abiraterone plus prednisone combination was similar to what was previously reported,” Dr. Fizazi said. Grade 3/4 hypertension was more common with abiraterone (20% vs. 10.2%), as was hypokalemia (10.8% vs. 1.2%), and increased alanine transaminase (5.3% vs. 1.0%). Adverse events leading to treatment discontinuation were relatively infrequent, at 12% with abiraterone and 10% in the control group; only two patients discontinued abiraterone because of hypokalemia. During the Press Briefing, Dr. Fizazi suggested caution when considering this therapy in men at increased cardiac risk.
“In my opinion, this finding supports the fact that adding abiraterone and prednisone to castration should now be considered as the new standard of care for these men with high-risk, newly diagnosed metastatic prostate cancer,” Dr. Fizazi concluded. Results of both STAMPEDE and LATITUDE were published immediately following the Plenary Session in the New England Journal of Medicine.
Dr. Eric J. Small discusses LBA3.
“Abiraterone brings the same or greater level of effectiveness against prostate cancer with far fewer side effects [than chemotherapy],” Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center, said during the Press Briefing about the LATITUDE trial. “These 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 noted the advantages that this therapy has over other options. The CHAARTED study and an earlier report of the STAMPEDE trial, published in 2015 and 2016, respectively, showed that adding chemotherapy to ADT offered a survival benefit, but chemotherapy carries significant risk of toxicity.
Eric J. Small, MD, FASCO, of the University of California, San Francisco, was the discussant for the LATITUDE study during the Plenary Session. He agreed that this was a “profoundly positive study,” though it may be more appropriate to compare the abiraterone regimen with ADT plus docetaxel. LATITUDE was fully accrued before the CHAARTED and other results were reported, so this comparison was appropriate given the available information.
Dr. Small also pointed out that there is no biologically plausible reason that the impact of adding abiraterone to ADT would be dependent on the risk criteria used in LATITUDE, and that there may be a benefit to testing the therapy in all patients with metastatic prostate cancer.
All the discussants commented that further investigation, such as a head-to-head comparison, is now needed to determine if ADT plus abiraterone provides similar or greater benefits compared with ADT plus docetaxel, and whether chemotherapy will still play a role in this setting for selected patients.
–Tim Donald, ELS, and Dave Levitan