More Is Not Better in Metastatic CR Prostate Cancer

Combo vs Single Agent

Pam Harrison

June 05, 2019

CHICAGO — More is not better when it comes to inhibition of the androgen receptor in men with metastatic castration-resistant prostate cancer (mCRPC), the Alliance study shows.

Indeed, treating patients with both enzalutamide (Xtandi, Astellas) and abiraterone (multiple brands) produces no further anticancer activity than treating them with enzalutamide alone, and it essentially doubles the adverse event (AE) rate compared to the single-agent approach.

"We hypothesized that dual inhibition of the androgen receptor signaling [pathway] by different mechanisms of action would improve the antitumor effects of the regimen," said study author Michael Morris, MD, Memorial Sloan-Kettering Cancer Center, New York City.

"But we conclude that adding abiraterone to enzalutamide does not improve overall survival [OS] relative to enzalutamide alone, and the current standard of care should not be changed by this study," he emphasized.

The study was presented here at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting.

The study was conducted in men with progressive MCRPC; 657 men were randomly assigned to receive enzalutamide, and 654 patients were allocated to receive enzalutamide plus abiraterone.

Enzalutamide was given at a dosage of 160 mg/day. Those in the combination arm received abiraterone 1000 mg/day and prednisone 5 mg twice daily.

Patients in the two treatment arms were well balanced in terms of age, performance status, race, and risk group, Morris pointed out.

Disease characteristics were also well matched between the two treatment arms; 56.8% of enzalutamide recipients and 54% of those treated with abiraterone had disease of Gleason grade 8, 9, or 10.

"At a median of 34.2 months in the enzalutamide-plus-abiraterone arm and 32.5 months in the enzalutamide-alone arm, there was no difference in OS between the two arms," Morris reported.

Radiographic progression-free survival (rPFS) rates were modestly in favor of the doublet arm, at 33%, compared with 42% for the single-agent arm.

The median on-treatment rPFS rate was 25.2 months for the doublet arm and 20.7 months for the single-agent arm. There was thus a modest improvement with the addition of abiraterone (P = .02), Morris noted.

Similarly, there was a modest improvement in the median on-treatment and off-treatment rPFS rate of 25.2 months for enzalutamide plus abiraterone, vs 22.4 months for enzalutamide alone, but again, these differences were "nothing to write home about" and were barely statistically significant (P = .05), he commented.

Rates of decline in prostatic-specific antigen levels were also similar between the two arms.

"The number one reason for patients coming off treatment was radiographic progression," Morris noted.

On the other hand, slightly fewer than 20% of patients in each arm experienced clinical progression before there was evidence of radiographic progression; these patients came off treatment because of clinical progression, he added.

Adverse Events Rate Higher With Combo

Among the patients who received the combination therapy, the withdrawal rate from treatment because of AEs was more than double that of the patients who received enzalutamide alone, Morris continued.

For example, the rate of grade 3 or 4 fatigue was 11.4% in the combination arm, vs 6.2% in the enzalutamide arm.

The rate of grade 3 or 4 hypertension was also higher, at 30.1%, for patients who received enzalutamide plus abiraterone, compared with 22.6% for the single-agent arm.

The atrial fibrillation rate, although low in both arms, was higher, at 1.1%, for the doublet arm, vs 0.5% for single-agent enzalutamide. Increases in levels of liver enzymes also occurred in more of the patients who were given the combination, at 8.6%, vs 2.2% for those treated with enzalutamide alone.

In total, 68.5% of patients in the enzalutamide-plus-abiraterone arm experienced a grade 3 or 4 nonhematologic AE, compared to 56.6% for those who received enzalutamide alone.

Despite the greater risk for AEs in the combination arm, "the median difference in treatment duration between the two arms was 51 days, so not that big a difference between the two arms, those receiving enzalutamide having a longer duration of treatment," Morris said.

"And the likely reason why this trial ended up being a negative study was simply that there was not much more anticancer activity in one arm vs the other," he concluded.

Important Study

Commenting on the findings, discussant Michael Carducci, MD, AEGON professor in prostate cancer research, Hopkins Kimmel Cancer Center, Baltimore, Maryland, felt that Alliance was an important study in which "timely" and "significant" questions for clinical practice were addressed.

"We know that there are patients who have fast-paced disease, so we do need to develop new drugs based on targets and their molecular features, but we also have to be mindful that if we overtreat patients and give them more therapy, we can make the time they have left actually fairly miserable," Carducci said.

"So while both of these drugs have the ability to extend survival, they can take a toll on quality of life as well as cost, so we have to make sure that we put it all together for our patients," he added.

Also commenting on the findings, Celestia Higano, MD, professor of medicine and urology, University of Washington, Seattle, noted that enzalutamide and abiraterone have different mechanisms of action and different resistance mechanisms, "so it certainly made sense to study this combination."

However, because the addition of abiraterone to enzalutamide did not improve OS, "we should not do that" in clinical practice, Higano emphasized.

"And while this was a negative trial, I think it's an example of how a negative trial can be very useful for us clinically," she said.

Morris has served as a consultant or on the advisory board for Advanced Accelerator Applications, Astellas Pharma, Bayer, Blue Earth Diagnostics, Endocyte, Tokai Pharmaceuticals, and Tolmar Pharmaceuticals. He also has received research funding from Bayer, Corcept Therapeutics, Endocyte, Progenics, Roche/Genentech, and Sanofi, has received travel expenses from Bayer and Endocyte, and has participated in the speaker's bureau for Oric. Carducci has served as a consultant for Pfizer, Roche/Genentech/Foundation Medicine, and AbbVie and has received research funding from EMD Serrano, Pfizer, and Effector. Higano has served as a consultant or on the advisory board for Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Janssen, Myriad Genetics, Pfizer, and Tolmar. She has also received research funding 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.

American Society of Clinical Oncology (ASCO) 2019 Annual Meeting: Abstract 5008. Presented May 31, 2019.

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