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CHICAGO – The Alliance study shows that androgen receptor inhibition is not better in men with metastatic castration-resistant prostate cancer (mCRPC).
Indeed, treating patients with both enzalutamide (Xtandi, Astellas) and abiraterone (Xtandi, Astellas) does not produce anticancer activity other than that of treating them with enzalutamide alone, and essentially doubles the rate of adverse events (AEs) compared to a single agent approach.
"We hypothesized that dual inhibition of androgen receptor signaling [pathway] by different mechanisms of action would improve the antitumor effects of the treatment regimen, "said study author, Michael Morris, MD, of the Memorial Sloan-Kettering Cancer Center in New York.
"But we conclude that the addition of abiraterone to enzalutamide does not improve overall survival [OS] compared to enzalutamide alone, and this study should not change the current treatment, "he said.
The study was presented here at the 2019 annual meeting of the ASCO (American Society of Clinical Oncology).
The study was conducted in men with progressive MCRPC; 657 men were randomly assigned to receive enzalutamide and 654 patients received enzalutamide plus abiraterone.
Enzalutamide was administered at 160 mg / day. Patients in the group receiving the combination received 1000 mg of abiraterone a day and 5 mg of prednisone twice a day.
Patients in both treatment arms were well balanced in terms of age, performance status, race and risk group, Morris said.
The characteristics of the disease were also well adjusted between the two treatment arms; 56.8% of the recipients of enzalutamide and 54% of those treated with abiraterone had Gleason grade 8, 9 or 10 disease.
"At a median of 34.2 months in the enzalutamide plus abiraterone arm and 32.5 months in the enzalutamide arm alone, there was no difference in bone between the two arms," he said. Morris.
Radiographic progression-free survival rates (rPFS) were slightly in favor of the doublet group at 33%, compared to 42% for the single-agent group.
The median RFS rate during treatment was 25.2 months for the doublet arm and 20.7 months for the single agent arm. The addition of abiraterone (P = 0.02), noted Morris.
Similarly, there was a slight improvement in the median RFS rate in treatment and outpatient treatment of 25.2 months for enzalutamide plus abiraterone, compared to 22.4 months for enzalutamide. alone, but again, these differences constituted "nothing incredible" statistically significant (P = 0.05), he commented.
Rates of decline in prostate specific antigen levels were also similar between the two arms.
"The main reason for stopping patient treatment was radiographic progression," noted Morris.
In addition, just under 20% of patients in each arm experienced clinical progression before signs of radiographic progression were evident. these patients have stopped their treatment due to the clinical course, he added.
Higher adverse event rate with Combo
Among the patients who received the combination, the rate of discontinuation of treatment due to adverse events was more than double that of patients who received enzalutamide alone, Morris continued.
For example, the grade 3 or 4 fatigue rate was 11.4% in the combined group compared to 6.2% in the enzalutamide group.
The grade 3 or 4 hypertension rate was also higher at 30.1% in patients treated with enzalutamide and abiraterone, compared to 22.6% for the group receiving single agent.
The atrial fibrillation rate, although low in both arms, was higher at 1.1% for the doublet group versus 0.5% for enzalutamide alone. Increases in liver enzyme levels also occurred in a larger number of patients receiving the combination, at 8.6%, compared to 2.2% for those treated with enzalutamide alone.
A total of 68.5% of the patients in the enzalutamide-abiraterone group experienced Grade 3 or 4 non-haematological AE, compared with 56.6% of those receiving enzalutamide alone.
Despite the higher risk of adverse events in the group receiving the combination, "the median difference in treatment duration between the two groups was 51 days, so the difference between the two groups is minimal, the patients receiving enzalutamide with a longer duration of treatment, "Morris said.
"And the probable reason why this trial ended up being a negative study was simply that there was not much more anticancer activity in one arm than the other." he concluded.
Important study
In commenting on the findings, commentator Michael Carducci, MD, professor at the AEGO Prostate Cancer Research Center, Hopkins Kimmel Cancer Center, Baltimore, Maryland, felt that the Alliance was an important study in which "timely" and "important" questions for clinical practice were addressed.
"We know that some patients have a fast-paced disease, so we need to develop new drugs based on their targets and their molecular characteristics, but we also need to be aware that if we over-treat patients and give them more treatment, we can: make the time they have left actually quite miserable, "said Carducci.
"So, while these two drugs can prolong survival, they can affect quality of life and cost, so we need to make sure everything is set up for our patients," he added.
By the way, Celestia Higano, MD, professor of medicine and urology at the University of Washington in Seattle, pointed out that enzalutamide and abiraterone had mechanisms of action and different resistance mechanisms, "so it made sense to study this combination".
However, as the addition of abiraterone to enzalutamide has not improved the SG, "we should not do that" in clinical practice, Higano said.
"And although it's a negative test, I think it's an example of how a negative test can be very helpful to us clinically," he said. she said.
Morris has been a consultant or advisory board member for advanced acceleration applications, Astellas Pharma, Bayer, Blue Earth Diagnostics, Endocyte, Tokai Pharmaceuticals and Tolmar Pharmaceuticals. He also received research funding from Bayer, Corcept Therapeutics, Endocyte, Progenics, Roche / Genentech and Sanofi, travel expenses from Bayer and Endocyte and participated in the Oric lecturer. Carducci has been a consultant for Pfizer, Roche / Genentech / Foundation Medicine and AbbVie and has received research funding from EMD Serrano, Pfizer and Effector. Higano has been a consultant or advisory board member of Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Janssen, Myriad Genetics, Pfizer and Tolmar. She has also received research funds from Aragon Pharmaceuticals, Astellas, AstraZeneca, Bayer, Dendreon, Emergent Biosolutions, Hinova Pharmaceuticals, Medivation and Pfizer and travel expenses from Astellas, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring , Hinova Pharmaceuticals, Menarini, Myriad Genetics and Pfizer.
2019 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract 5008. Presented May 31, 2019.
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