1. Goodwin, Peter M.

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CHICAGO-The androgen synthesis inhibitor abiraterone reduced the risk of death when added to initial hormone therapy for men newly diagnosed with high-risk prostate cancer in a study reported at the 2017 ASCO Annual Meeting, held June 2-6.

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A significant survival advantage in favor of adding abiraterone emerged from the multi-arm multistage STAMPEDE trial in which 1,917 patients with locally advanced or metastatic prostate cancer were randomized to a control group receiving the current standard of care (consisting of androgen deprivation therapy (ADT) with or without radiotherapy) or an investigational arm treated identically but with abiraterone added.


Longer Survival

"Abiraterone not only prolonged life, but also lowered the chance of relapse by 70 percent and reduced the chance of serious bone complications by 50 percent," noted Nicholas D. James, MBBS, PhD, FRCR, FRCP, Professor of Clinical Oncology at the University of Birmingham and Consultant Clinical Oncologist at Queen Elizabeth Hospital, Birmingham, U.K., and lead author of the Swiss-British study (Abstract LBA5003).


The study tested additional drugs in men starting long-term hormone therapy for the first time. "This was formalized into men with high-risk, locally-advanced disease who haven't had a prior hormone therapy-so high T-stage, node-positive disease, or men with de novo metastatic disease."


Treatment consisted of at least 2 years of hormone therapy plus abiraterone in the investigational arm. In addition to ADT, radiotherapy was mandated in all men with "prostate only" disease and it was encouraged in those with positive nodes. Around half of the patients in each group had metastases.


Use Sooner

James said they needed to know if abiraterone could be even more effective if used sooner in the course of prostate cancer rather than waiting for patients to relapse. "Instead of using your treatments one after the other, you use one or more of them upfront-from the get-go, basically."


After 40 months median follow-up, there had been 262 deaths in the control arm and 184 in patients receiving abiraterone. At 3 years, the overall survival rates were 83 percent with abiraterone and 76 percent without.


"The overall hazard ratio for survival was 0.63. That's a 37 percent improvement in survival," stated James, adding that median overall survival had not been reached, but that "projecting" data that were not yet mature indicated an increase from just over 3 to around 6.5 years. "For failure-free survival, we've got a hazard ratio of around 0.3 in favor of upfront abiraterone-a 70 percent improvement, which is colossal-huge.


"For symptomatic skeletal events such as pain, pathological fracture, radiotherapy, [and] spinal cord compression, there was a 55 percent reduction," continued James, describing this as "huge, highly clinically significant, very important to patients, and probably very important to cost-effectiveness"-potentially avoiding events that were expensive as well as unpleasant.


STAMPEDE and other studies had previously established that adding docetaxel to standard care at the time of initial hormone therapy in this patient group brought a 25 percent improvement in survival. "The new data provide evidence that abiraterone also improved outcomes and this finding [also] supports a change of practice," James noted.


Lower Relapse Rates

James was impressed by the powerful effect abiraterone had on reducing relapse rates in men who had high-risk primary disease. "What we know from older studies is that, if we just manage high-risk patients with hormone therapy, half of them will progress to metastatic disease by 3 years. So they are on a spectrum of disease that with standard hormone therapy is deemed to progress to metastatic disease. Now what we're seeing is that if we add radiotherapy to that-and then add things like docetaxel or abiraterone on top of it-we are seeing relapse rates drop to very low levels indeed," he explained.


Around a quarter of patients with non-metastatic disease who received only ADT plus radiotherapy had relapsed at 3 years. "This drops to under 5 percent if you add abiraterone on top. So in 3 years, we've seen [a] 25 percent relapse [rate] drop to less than 5 percent."


James regarded the use of upfront abiraterone as a "game changer." "We've seen effects the like of which I've never seen before in a clinical trial-and I don't think anybody else has either. So they certainly deserve to change practice and are so big that cost-effectiveness will probably turn out to be affordable and justifiable."


Although he could not say whether docetaxel or abiraterone should be chosen by any individual patient, James was interested in using both agents in the same patient. "If we've got a 25 percent survival gain with docetaxel and another 30 percent gain with abiraterone, might you get both benefits if you gave both treatments?" He said this raised the possibility of increasing survival rates for metastatic prostate cancer-maybe-to 10 years, which he described as "absolutely transformational."


Managing Toxicity

But with higher toxicity from abiraterone, patients needed more monitoring. "You've got a significant rate of hypertension," he said. In some patients, treatment was stopped because of alterations of liver enzymes. And there were some deaths as with docetaxel. "Given that there are cardiovascular side effects and [that] we're treating an elderly population, it may well be that some patients are being harmed by the treatment. But for most patients it's a relatively low-toxicity pill to take. They don't notice the hypertension-it's just that they have to have pills for it if they get it," James noted.


"Based on the magnitude of clinical benefit, we believe that the upfront care for patients newly diagnosed with advanced prostate cancer should change."


Commenting on the data ASCO spokesperson, Sumanta Kumar Pal, MD, Associate Professor of Oncology at City of Hope, Duarte, Calif., said that STAMPEDE added to a "growing body of evidence that establishes abiraterone as a standard of care in this setting." But he wasn't sure the case for adding it to initial therapy was yet proven in the non-metastatic setting.


"It becomes abundantly clear that abiraterone is a very reasonable option for patients with metastatic prostate cancer. The grey area that remains is the benefit that might exist in patients with non-metastatic prostate cancer. For that, I really think we need further study. It's important to point out that [this] study incorporates two very different patient populations and the outcomes for these groups vary. It's possible that with longer follow-up outcomes for patients with non-metastatic prostate cancer may trend towards significance. But at the present time, I would utilize [these] results primarily to apply to a metastatic prostate cancer population," he concluded.


Peter M. Goodwin is a contributing writer.