SAN FRANCISCO – Men with metastatic hormone-naive prostate cancer have better outcomes when given the nonsteroidal anti-inflammatory drug celecoxib and the bisphosphonate zoledronic acid in addition to standard therapy, according to data from the randomized STAMPEDE trial.
The 1,245 men treated on three trial arms had high-risk locally advanced or metastatic prostate cancer and had not previously received any hormone therapy.
Dr. Nicholas D. James
Prespecified analyses showed that when added to standard of care (androgen deprivation therapy and, optionally, radiation therapy), neither celecoxib alone nor the combination of celecoxib and zoledronic acid improved outcomes in the entire trial population, Dr. Nicholas D. James reported at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. But among men who had metastases at baseline, the combination reduced the risk of failure-free survival events by 23% and the risk of death by 24%.
“At the very least, we feel that this data merits further evaluation, particularly as these drugs are widely used and widely available,” commented Dr. James, director of the cancer research unit at the University of Warwick, Coventry, England.
The findings help provide a big picture when viewed together with those from previously reported STAMPEDE trial arms that tested addition of docetaxel (found effective) and of zoledronic acid alone (found ineffective), he noted (Lancet. 2015 Dec 21).
“It does look as though there is a possibility of [a] synergistic or an additive effect here” of celecoxib and zoledronic acid in the patients with metastases, he said. Also, the magnitude of benefit with the combination was similar to that of docetaxel when it came to overall survival, albeit somewhat less when it came to failure-free survival.
Dr. A. Oliver Sartor
Invited discussant Dr. A. Oliver Sartor, the Laborde Professor for Cancer Research and medical director at the Tulane Cancer Center in New Orleans, commented, “We now know from a number of studies that docetaxel and ADT [androgen deprivation therapy] prolong survival, and I believe it should be the standard of care for ‘chemo-fit’ patients with metastatic hormone-sensitive disease.”
Implications of the new findings are unclear, he said. “Neither zoledronic acid nor celecoxib is standard of care today within these hormone-sensitive patients, and I just suspect this combination is unlikely to become standard of care going forward.” In particular, celecoxib has a black box warning for cardiovascular events, which makes its use problematic in the litigious U.S. environment.
At the end of the day, there are likely higher-priority research questions to be addressed in hormone-sensitive disease, according to Dr. Sartor. “Abiraterone, enzalutamide, and radium all need testing,” he said. “And from a global perspective, this disease state is incredibly important. North America and Western Europe are not really the center of the universe. There are lots of people out there who get diagnosed with hormone-sensitive metastatic disease, and they need better therapies than ADT, which is the standard worldwide.”
Giving some background to the research, Dr. James explained that zoledronic acid (Zometa) was chosen because it is known to reduce skeletal-related events in men with bone metastases of castration-refractory disease and was being studied for prevention of metastases. Celecoxib (Celebrex) was chosen in part because it inhibits cyclo-oxygenase-2 (COX-2), which is associated with tumor growth and invasiveness, along with epidemiologic data linking use of nonsteroidal anti-inflammatory drugs with lower prostate cancer risk.
The new analyses were based on 622 men who received only standard of care, 312 who additionally received celecoxib, and 311 who additionally received celecoxib plus zoledronic acid. Overall, 61% had metastases at baseline.
With a median follow-up of 63 months, 55% of men were alive, 36% had died of prostate cancer, and 9% had died of other causes, Dr. James reported.
The addition of celecoxib alone did not improve failure-free survival or overall survival, compared with standard of care alone, either in the whole trial population or in the subgroups with and without metastases.
And the addition of both celecoxib and zoledronic acid did not improve either outcome in the entire trial population overall. But here, there were interaction trends according to the presence of metastases.
Patients with metastases who received celecoxib and zoledronic acid had reductions in the risks of failure-free survival events (hazard ratio, 0.77; P = .008) and overall survival events (hazard ratio, 0.78; P = .04) relative to peers who received standard of care alone. In contrast, patients without metastases did not benefit.
Adverse events of grades 3-5 occurred in about one-third of patients in each treatment arm, with no significant differences in incidence. “In particular, for cardiac disorders, there is no evidence of cardiac toxicity,” Dr. James noted. “But we had excluded patients with a significant history of MIs, heart failure, and so on, so these are patients with a good cardiovascular status going into the trial.”