Abiraterone Improves Survival for Some Men with Hormone-Sensitive Prostate Cancer

June 19, 2017, by NCI Staff

Results from two large clinical trials may change how some men with metastatic prostate cancer are treated. Both trials showed that adding the hormone-blocking drug abiraterone (Zytiga®) to standard androgen-deprivation therapy (ADT) allowed men with metastatic hormone-sensitiveprostate cancer to live longer than if they were treated with ADT alone.

Results from both trials, presented at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3 and 4, 2017, will likely have an immediate impact on patient care, oncologists at the meeting agreed.

Currently, the standard of care in the United States for these men is ADT plus the chemotherapy drug docetaxel. But some patients—especially those who are older and have additional health issues—cannot tolerate that combination.

“Abiraterone…offers a great alternative for those individuals who may not be great candidates for or decline chemotherapy,” commented Sumanta Kumar Pal, M.D., of City of Hope, who specializes in the treatment of prostate and other urologic cancers, at the ASCO meeting.

Full results from the two trials, called LATITUDE and STAMPEDE, were published June 3 in the New England Journal of Medicine.

Moving Abiraterone Upfront

Doctors currently use abiraterone to treat metastatic prostate cancer that has developed resistance to standard hormone therapy (called castration-resistant prostate cancer). The LATITUDE and STAMPEDE trials both studied whether the drug has benefits if used earlier in treatment. LATITUDE was funded in full and STAMPEDE in part by Janssen Research and Development, the manufacturer of abiraterone.

LATITUDE included 1,199 men who had newly diagnosed metastatic prostate cancer and at least two of three other factors associated with a poor prognosis: a Gleason score of 8 or higher; at least three metastatic lesions in the bones; and measurable metastases in visceral organs (such as the liver).

Participants were randomly assigned to receive either ADT, abiraterone, and the steroid prednisone or ADT plus two placebos. (Treatment with abiraterone, which works by disrupting the production of testosterone, can increase blood pressure and decrease potassium levels. So prednisone is always given along with abiraterone to reduce the risk of these side effects.)

At a median follow-up of just over 30 months, men receiving abiraterone in addition to ADT had a 38% lower risk of death from any cause than those receiving ADT alone. Men in the abiraterone group also went longer before the pain from their metastases worsened; they developed bone complications, such as fractures and spinal-cord compression; and they needed subsequent therapy for their cancer.

STAMPEDE, which has been ongoing since 2005, has sequentially tested several different treatments added to ADT for men with high-risk hormone-sensitive prostate cancer who have not previously received hormone therapy. Results from an earlier round of the trial, which added docetaxel to ADT, contributed to that combination becoming the current standard of care.

In the most recently completed stage of the trial, 1,917 men were randomly assigned to receive abiraterone plus prednisone and ADT, or ADT alone. Radiation therapy was also used for about 40% of patients in both groups. Only about half of the men in this trial had metastatic disease. Another 20% had nonmetastatic disease that had spread to lymph nodes near the prostate, and the rest had nonmetastatic disease that had not spread to the lymph nodes but had high-risk features that strongly suggested the cancer could develop into metastatic disease.

At a median follow-up of 40 months, men receiving the combination of abiraterone plus ADT had a 37% improvement in overall survival compared with men who received ADT plus placebos. The improvement in survival was seen both in metastatic and nonmetastatic disease.

Men in the abiraterone group also had a 54% reduction in the risk of bone complications, including pain and damage to the spinal cord. “This is extremely important to patients and very good news,” said Nicholas James, M.B.B.S., Ph.D., of Queen Elizabeth Hospital Birmingham in the United Kingdom, who presented the STAMPEDE data at ASCO.

In both trials, the incidence of serious side effects was somewhat higher in the men who received abiraterone than in the men who received ADT alone: 63% versus 48% in LATITUDE and 47% versus 33% in STAMPEDE. Men receiving abiraterone were more likely to experience increases in blood pressure, low potassium levels in the blood, elevated levels of liver enzymes, and breathing problems.

Open Questions

The results from the two trials “support that…adding abiraterone plus prednisone [to ADT] should be considered the new standard of care in men with newly diagnosed prostate cancer with high metastatic burden,” said Karim Fizazi, M.D., Ph.D., of the University of Paris-Sud in France and lead author of the published paper on the LATITUDE trial, at the meeting.

But neither trial directly compared abiraterone plus ADT to docetaxel plus ADT, cautioned Ravi Madan, M.D., clinical director of the Genitourinary Malignancies Branch in NCI’s Center for Cancer Research.

“While the [abiraterone] data are exciting, there is no clear evidence that [either] abiraterone or docetaxel is superior for patients with metastatic, castration-sensitive disease,” said Dr. Madan. “Therefore, both are options for this population. It may be preferred to tailor treatment to patients based on patient preferences and comorbidities.”

One consideration will be the side effects of the two agents. However, comparing side effect profiles between docetaxel and abiraterone is an “apples and oranges” comparison, explained Dr. James, because docetaxel treatment is short-term and abiraterone is given continuously for years.

“Docetaxel is associated with more side effects, including infrequent but serious side effects such as febrile neutropenia and neuropathy. But most of these side effects are often reversible,” and the drug is given in six infusions over only 18 weeks, added Dr. Madan.

Long-term abiraterone use has been associated with increased hypertension and liver toxicity over time, and the accompanying prednisone could also produce long-term side effects, such as reduced bone mineral density, he continued.

STAMPEDE is now enrolling participants into arms of the trial that are directly comparing abiraterone plus ADT versus docetaxel plus ADT, said Dr. James at the ASCO meeting. In the future, other trials may also look at the three therapies—abiraterone, docetaxel, and ADT—given together or sequentially.

Longer-term data from STAMPEDE will also help indicate whether abiraterone plus ADT should be the new standard of care in men with high-risk, nonmetastatic disease.

In STAMPEDE, the same magnitude of benefit on overall survival was seen in men with and without metastases at diagnosis, explained Dr. James. However, relatively few enrolled men with nonmetastatic disease have died to date.

The definitive answer to whether these men have improved overall survival with the addition of abiraterone “will sort itself out as patients are followed longer,” commented Richard Schilsky, M.D., chief medical officer for ASCO, at the meeting.

In the meantime, Dr. Madan said, the STAMPEDE data “do provide a rationale for [using abiraterone] in these other high-risk populations.”