Posted without comment for the SOC crowd.
Emmanuel Antonarakis, MD, on Dual Androgen Receptor Inhibition in Metastatic Castration-Resistant Prostate Cancer– 'Combination of two androgen-directed agents should not be utilized in clinical practice at this time', MedPage Today, ASCO > Prostate Cancer, by Jeff Minerd , Contributing Writer, July 20, 2023.
A phase III trial found no survival benefit for the combination of enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer, but it did find something else noteworthy.
A pharmacokinetic analysis found that the clearance rate of abiraterone was two to three times higher when administered with enzalutamide, Michael Morris, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues reported in the Journal of Clinical Oncology.
They said that although that pharmacokinetic effect might have blunted the clinical impact of the combination on survival, it did not prevent the combination from having more side effects than use of enzalutamide alone.
The two drugs use different mechanisms to target androgen receptor signaling, and the researchers had hoped the combination would overcome drug resistance. Abiraterone targets extra-gonadal androgen synthesis, while enzalutamide directly targets the androgen receptor.
In the following interview, co-author Emmanuel Antonarakis, MD, endowed professor and associate director of Translational Research at the Masonic Cancer Center of the University of Minnesota in Minneapolis, elaborated on the findings.
What possible mechanism or mechanisms might underlie the increased clearance rate of abiraterone when given with enzalutamide?
Antonarakis: Although the exact mechanism is incompletely understood, it is known that enzalutamide is a strong inducer of the CYP3A4 enzyme that can affect the circulating concentrations of other drugs that are metabolized by it. Since abiraterone is a substrate of CYP3A4, induction of this enzyme by enzalutamide leads to more rapid breakdown of abiraterone in this context.
Might a different combination of drugs that target androgen receptor signaling work better?
Antonarakis: I don't think so. I believe the main lesson from this study is that dual androgen receptor inhibition is not superior to monotherapy. In my opinion, it is unlikely that the drug-drug interaction was the primary reason that a survival benefit with combination therapy was not observed.
Radiographic progression-free survival was 3 months longer in patients treated with the combination, and the result was statistically significant. What is the clinical significance of this finding?
Antonarakis: Unfortunately, in the absence of a survival benefit, a slight prolongation of radiographic progression-free survival is not clinically meaningful, especially because the enzalutamide-abiraterone combination produced greater toxicity (fatigue, hypertension, liver dysfunction, arrhythmias).
A secondary objective of the trial was to assess the relationship between radiographic progression-free survival and overall survival. Why did you do this and what did the study find?
Antonarakis: This analysis was conducted in order to determine whether radiographic progression-free survival could potentially serve as an intermediate regulatory endpoint for future phase III trials in metastatic castration-resistant prostate cancer. This study, as well as others conducted by the Prostate Cancer Clinical Trials Working Group, have shown strong and consistent associations between progression-free and overall survival in the context of androgen receptor-targeting therapies. Thus, radiographic progression-free survival might be a reasonable primary endpoint in this setting moving forward.
Is there anything else you would like to make sure oncologists understand about this study or this topic?
Antonarakis: This has been the second study of combination androgen receptor-targeting therapy that has failed to show a survival benefit. A prior phase III study of abiraterone plus apalutamide versus abiraterone alone also showed a significant progression-free survival benefit without a corresponding survival benefit.
As a result of these two negative trials, enthusiasm has diminished for conducting additional studies combining androgen synthesis inhibitors with androgen receptor antagonists. The combination of two androgen-directed agents should not be utilized in clinical practice at this time. (emphasis added.)
MedPage article is here (It provides a link to a PDF download of the full paper):
Emmanuel Antonarakis, MD, on Dual Androgen Receptor Inhibition in Metastatic Castration-Resistant Prostate Cancer– 'Combination of two androgen-directed agents should not be utilized in clinical practice at this time', MedPage Today, ASCO > Prostate Cancer, by Jeff Minerd , Contributing Writer, July 20, 2023.
medpagetoday.com/reading-ro...
Seems to be one of those rare occasions when docs are saying less is more!
Stay S&W, Ciao - K9
