Kate Johnson

June 03, 2017

CHICAGO — New results with first-line use of abiraterone (Zytiga, Janssen) are set to transform the upfront treatment of advanced prostate cancer "practically overnight," based on results of the STAMPEDE and LATITUDE trials presented here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, according to Richard Schilsky, MD, chief medical officer at ASCO.

"These data will propel abiraterone into first-line use," Dr Schilsky predicted. At present, the drug is approved for use after failure of androgen deprivation therapy (ADT), but the new data show substantial benefit when used earlier on, in combination with ADT.

The findings "should change the treatment paradigm" in newly diagnosed disease, with abiraterone largely displacing chemotherapy from the current paradigm, predicted Sumanta Kumar Pal, MD, City of Hope Comprehensive Cancer Center, Duarte, California, another ASCO expert, during a press briefing.

Adding abiraterone to ADT hits the production of testosterone, which fuels prostate cancer, with a 'double whammy.' ADT works by preventing testosterone production in the testicles, but the adrenal glands and prostate cancer cells continue making small amounts of androgens. Abiraterone, a steroidal CYP17A1 inhibitor, stops production of testosterone throughout the body, reducing hormone levels still further.

Data presented today from the British STAMPEDE study (abstract LBA5003) in nearly 2000 patients show that when abiraterone (with prednisolone) was added to ADT it improved the 3-year survival rate to 83%, compared to 76% with ADT alone.

"We think this is one of the biggest survival benefits ever reported in a trial of an adult solid tumor," said lead investigator Nicholas James, MBBS, PhD, from Queen Elizabeth Hospital in Birmingham, UK.

Results from the LATITUDE trial (abstract LBA3) in nearly 1200 men show that abiraterone (plus prednisolone) added to ADT more than doubled median progression-free survival to 33 months, compared to 14.8 months with ADT alone. The full results will be presented June 4 during the plenary session, but were released to the press today with the STAMPEDE results, as the LATITUDE results are confirmatory.

"The benefit from early use of abiraterone we saw in this study is at least comparable to the benefit from docetaxel chemotherapy, which was observed in prior clinical trials, but abiraterone is much easier to tolerate, with many patients reporting no side effects," commented lead study author Karim Fizazi MD, PhD, head of the department of cancer medicine at Gustave Roussy, University Paris-Sud, Villejuif, France.

"These findings indicate that the addition of abiraterone (plus prednisolone) to ADT can potentially be considered a new standard of care for patients with high-risk, newly diagnosed metastatic prostate cancer," Dr Fizazi added.

Results from both phase 3 studies will be simultaneously published online in the New England Journal of Medicine (STAMPEDE today and LATITUDE tomorrow).

Overall Survival Benefit

STAMPEDE was conducted in 1917 men with hormone-naive advanced prostate cancer randomized to abiraterone plus prednisone together with ADT, or ADT alone.

The results show a "highly positive" 3-year overall survival (OS) rate of 83% vs 76%, corresponding with a 37% relative improvement in survival (HR, 0.63; P = 0.0000012) with the addition of abiraterone, reported Dr James.

About half (52%) of participants had metastatic disease. The survival benefit was similar in metastatic and nonmetastatic disease, he added.

Additionally, there was a "very impressive" 3-year failure-free survival rate of 75% in the treatment arm vs 45% with standard therapy, corresponding to a 71% relative improvement in time to treatment failure (HR, 0.29).

Adverse events were "similar to those seen in the relapse setting," he noted, drawing particular attention to skeletal-related events, for which there was a 55% reduction in the experimental arm. "We think this is extremely important to patients and very good news," Dr James said.

Similarly impressive results were also reported for the LATITUDE study, which will be presented later at the meeting.

In that study, among 1199 similar patients — all with newly diagnosed, high-risk metastatic prostate cancer — the addition of abiraterone to ADT resulted in a 38% lower mortality rate compared with ADT alone after a median follow-up of 30.4 months, Dr Fizazi noted.

However, several severe side effects were noted in the abiraterone group including high blood pressure (20% vs 10%), low potassium level (10.4% vs 1.3%), and liver enzyme abnormalities (5.5% vs 1.3%).

"It is remarkable to see the similarity in survival benefit across two studies in this population," commented Dr Pal.

"Hormone therapy using agents that suppress testosterone and/or its activity, have been the mainstay of metastatic prostate cancer for decades," he commented during the press briefing.

"A few years ago, the treatment paradigm for prostate cancer was shaken up by the CHAARTED study, which showed a survival benefit associated with the addition of chemotherapy to hormone therapy in this setting," he continued. These new data provide an important alternative to chemotherapy, namely the use of abiraterone.

"Although it is challenging to put the existing data for chemotherapy and abiraterone side by side, at first glance, it appears as though the benefit in survival mirrors or exceeds the benefit we have seen with abiraterone," Dr Pal commented. "But chemotherapy brought with it significant toxicities like nerve damage, fatigue, and decreases in blood counts that are often very difficult for patients to handle. Abiraterone brings the same level or greater levels of effectiveness against prostate cancer with far fewer side effects."

"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 disease," he said.

Other experts also welcomed the new data.

"The results from LATITUDE and STAMPEDE provide important and likely practicing-changing information," commented Thomas Flaig, MD, from the University of Colorado School of Medicine, when contacted by Medscape Medical News.

"These data are certainly impressive and unambiguous, and will no doubt contribute to the evolving standard of care for patients presenting with metastatic disease," agreed Charles Ryan, MD, from the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center. "While broadening the duration and proportion of those who benefit from hormone therapy, the study also highlights the need for the research community to continue to address the mechanisms of hormonal resistance, which still emerged in most patients."

Matthew R. Zibelman, MD, assistant professor in the department of hematology and oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania, commented: "Standard of care for this patient group is currently chemotherapy. The real benefit here [is that] in addition to chemotherapy, in the highest risk patients, we now have an oral option that may have less toxicity with similar long-term benefit in patients with newly diagnosed metastatic, castrate-sensitive prostate cancer."

However, Otis Brawley, MD, chief medical and scientific officer of the American Cancer Society, cautioned against jumping too quickly to conclusions.

"Hormonal therapy for prostate cancer causes cardiac disease, and there are some of us who for a long time have been worried that some of the decline in prostate cancer mortality is actually a transference of cause of death to heart disease. It's actually been shown in every hormonal therapy that we see in prostate cancer," he said.

"For me the challenge is to realize there's a double-edged sword. I will be using these drugs to treat my prostate cancer patients, but I'm going to be selective. For patients who have a history of diabetes or coronary artery disease, perhaps not. There's going to be patient demand because of the wonderful things that are being said — and keep in mind I'm acknowledging some of those wonderful things are wonderful, but we as doctors have to be very careful."

2017 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract LBA5003 (STAMPEDE) was presented June 3, 2017. Abstract LBA3  (LATITUDE), presented June 4, 2017.

The STAMPEDE study was funded by Cancer Research UK, Medical Research Council, and Janssen, with additional contributions from Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. Dr James disclosed consulting or an advisory role with Sanofi, Bayer, Merck, Astellas, Janssen; serving on a speakers’ bureau for Pierre Fabre, Ferring, Sanofi, Astellas; receiving honoraria from Sanofi, Bayer, OncoGeneX, Janssen, Astellas, Pierre Fabre; research funding (institutional) from Janssen, Astellas, Pfizer, Sanofi, Novartis. Dr. Flaig was not directly involved in either trial but disclosed having served as a local primary investigator and has received funds from Cougar/Janssen for clinical trial related expenses for other abiraterone trials. Dr Ryan disclosed advising and receiving honoraria from Janssen.

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