CHICAGO – It's no longer better when it comes to inhibiting the androgen receptor in men with metastatic castration-resistant prostate cancer (mCRPC), according to the Alliance study.
Indeed, treating patients with enzalutamide (Xtandi, Astelas) and abiberatone (Xtandi, Astelas) does not produce further anticancer activity than to treat it alone with enalutamide, and essentially doubles the rate of adverse effects (AE) compared with an agent approach.
"We hypothesized that dual inhibition of the androgen receptor signaling [pathway] with different mechanisms of action will improve the antitumour effects of the regime, "says study author Michael Morris, MD, Slon-Kettering Memorial Center for Cancer, New York.
"But we conclude that adding abalaterone to enalumumide does not improve overall survival [OS] in relation to the enalutamide itself, and the current standard of care should not be changed with this study, "he noted.
The study was presented here at the Annual Meeting of the American Association of Clinical Oncology (ASCO) in 2019.
The study was conducted in men with progressive MCRPC; 657 men were randomly assigned to receive enalumumide, and 654 patients were prescribed to receive enalumumide plus abyterterone.
Ecetalumide was given at a dose of 160 mg / day. Those in combination therapy received abiraterone 1000 mg / day and prednisone 5 mg twice daily.
Patients in both treated hands were well balanced in terms of age, status, race and risk group, said Morris.
The characteristics of the disease were also well aligned between the two treated hands; 56.8% of the recipients of enalumumide and 54% of those treated with abyteratone had a Glyson disease of 8, 9 or 10 degrees.
"In the mean value of 34.2 months in the enalumumide-plus-abyteronone group and 32.5 months in the single enalutamide group, there was no difference in OS between the two arms," Morris said.
The rate of radiographic progression-free survival (rPFS) was modest in favor of the double arm, at 33%, compared to 42% for the single agent group.
The median rate of rPFS for treatment was 25.2 months for the double arm and 20.7 months for arm with single agent. Thus there was a modest improvement with the addition of abiraterone (P = .02), noted Morris.
Similarly, there was a modest improvement in the mean rPFS rate for treatment and treatment of 25,2 month offtranium for enalumumide plus apiréterone versus 22,4 months for enalumutide only, but these differences were not "nothing to write home" and barely statistically significant (P = 0.05), he commented.
The rates of decline in the levels of specific antigen for prostate were also similar between the two arms.
"The first reason for the patients who left the treatment was radiographic progression," said Maurice.
On the other hand, fewer than 20% of patients in each group had clinical progression before there was evidence of radiographic progression; these patients got out of the treatment due to clinical progression, he added.
Unwanted rates at a higher level with combo
Among patients who received combination therapy, the rate of withdrawal from treatment due to AE was more than double that in patients receiving only enalutamide, Morris continued.
For example, the grade 3 or 4 fatigue rate was 11.4% in the arm combination, compared to 6.2% in the enalumumide group.
The rate of grade 3 or 4 hypertension was also higher, in 30.1%, in patients receiving enalatumide plus abyterteron, compared with 22.6% for the single agent group.
The rate of atrial fibrillation, albeit low in both hands, was higher, to 1.1%, for the double arm, versus 0.5% for a single enalumutamide agent. An increase in the level of liver enzymes also occurred in more patients who received the combination, to 8.6% versus 2.2% in those treated with enalumumide alone.
In total, 68.5% of patients in the enalumutide-plus-abyteronone group had non-hematologic AE grade 3 or 4, compared with 56.6% in those receiving enalumumide alone.
Despite the greater risk for AE in the combined arm, "the average difference in the duration of treatment between the two arms was 51 days, so there is no big difference between the two arms, those receiving enalumumide with a longer treatment period," said Maurice.
"The most likely reason why this trial ended up as a negative study is simply that there was not much more anticancer activity in one hand versus the other," he concludes.
Commenting on the findings, Professor Miguel Carducci, professor of prostate cancer, Michael Carducci, the Hopkins Kimmel Cancer Center, Baltimore, Maryland, considered that the Alliance was an important study that covered "timely" and "significant" issues for the clinical practice.
"We know that there are patients who have a rapid illness, so we need to develop new drugs based on goals and their molecular characteristics, but we also need to be aware that if we transcribe patients and give them more therapy, we can make the time that they left him, in fact, quite unhappy, "Carducci said.
"So, while both drugs have the ability to extend survival, they can take a drop in quality of life as well as costs, so we have to make sure that we put them together for our patients," he added.
Also, commenting on the findings, Dr. Celestia Higano, MD, professor of medicine and urology, University of Washington, Seattle, noted that enalatumum and abiraterone have different mechanisms of action and different resistance mechanisms, "so it makes sense to study this combination ".
However, since the addition of abalaterone to enalumumide did not improve the operating system, "we should not do it" in clinical practice, Higano said.
"While this was a negative trial, I think it's an example of how negative examination can be very useful for us clinically," she said.
Morris works as a consultant or advisory board for advanced accelerator applications, Astellas Pharma, Bayer, Diagnostics of Blue Earth, Endocyte, Tokai Pharmaceuticals and Tolmar Pharmaceuticals. He also received funding from Bayer, Therapeutic Therapy, Endocyte, Progenix, Rosch / Gentenec and Sanofi, received travel expenses from Bayer and Endocytes and participated in the Oric's speaker's desk. He worked as a consultant for Pfizer, Roche / Genentech / Foundation Medicine and AbbVie and received a financial survey from EMD Serrano, Pfizer and Effector. Higano served as a consultant or advisory board for Astellas, AstraZeneca, Bayer, Diagnostics of the Blue Earth, Clovis Oncology, Ferring, Jasen, Miriad Genetics, Fischer and Tolmar. She also received research funding from Aragon Pharmaceuticals, Astellas, AstraZeneca, Bayer, Dendreon, Emergent Biosolutions, Hinova Pharmaceuticals, Medivation and Pfizer and travel costs from Astellas, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Menarini, Huge Genetics and Pfizer.
American Association for Clinical Oncology (ASCO) Annual Meeting 2019: Abstract 5008. Presented on May 31, 2019.
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