Panelists: Judd Moul, MD, Duke Cancer Institute; Neeraj Agarwal, MD, Hunstman Cancer Institute; Tanya Dorff, MD, City of Hope National Medical Center; Alicia Morgans, MD, PhD, Northwestern University Feinberg School of Medicine
Judd Moul, MD: I want to follow up on the comment about Fernand Labrie, MD, PhD, and flutamide. Flutamide was a first-generation nonsteroidal oral antiandrogen. Some people feel that nilutamide was also first generation, and many people believed that bicalutamide was second generation. It’s a little more potent, although that’s controversial. Now enzalutamide and apalutamide are third generation, and some people believe that darolutamide is fourth generation. You could argue that point. The interesting thing is that apalutamide is the first out of the gate to truly prove Labrie’s concept.
Neeraj Agarwal, MD: By 2 days.
Judd Moul, MD: Yes. We have this overall survival advantage. It’s combined androgen blockade with apalutamide at ASCO [American Society of Clinical Oncology Annual Meeting] 2019, and it truly proves the point that maximal androgen blockade improves overall survival. There’s no question about it. To follow up on your point, why do you say, “By 2 days?”
Neeraj Agarwal, MD: First of all, I was just joking. Apalutamide was presented 2 days before the ENZAMET trial. It’s a matter of how you look at who reported first. I think both reported at the same time. To make a comment on first generation and second generation, I don’t look at these drugs from that perspective. For me, 1 class contains nonspecific androgen receptor blockers, which include flutamide, nilutamide, bicalutamide. They block androgen receptors and don’t do anything beyond that.
Judd Moul, MD: Correct.
Neeraj Agarwal, MD: The second generation—I don’t even want to use the word generation. I want to use, direct, potent androgen receptor blockers. These are very specific, and they also interfere with the binding of the androgen receptor with the androgen receptor elements on the DNA. They go beyond the others. They also stop the translocation of the androgen receptor into the nucleus. It’s not only interaction with binding. They have other actions on androgen receptors. These are novel androgen receptor inhibitors. I was talking about agents like apalutamide. We have apalutamide, which clearly improves overall survival with a 33% reduction in death. That is very remarkable. I don’t think we can even compare the old-generation NSAAs [nonsteroidal antiandrogens] with apalutamide.
Judd Moul, MD: No, because flutamide got FDA approval in 1989 based on the 7-month survival advantage. To play devil’s advocate to myself, in that era, most of those patients were high-volume disease because that was right at the beginning of the PSA [prostate-specific antigen] era, and there was a lot of existing metastatic disease that came to the forefront because of PSA. It may be like comparing apples and oranges to compare patients 30 years ago to those now. There’s a big difference between a 7-month survival advantage, which barely had the confidence interval that made it statistically significant, and this quite significant difference in 2019.
Tanya Dorff, MD: It’s very important that in the ENZAMET trial, the control arm was not placebo. It was flutamide, nilutamide, or bicalutamide. We got a head-to-head comparison showing that this next generation of androgen receptor antagonists are truly more potent.
Neeraj Agarwal, MD: That’s a great point. Also, since the trial was published with flutamide 30 years ago, there were multiple other studies and meta-analyses that came up. The ASCO guidelines clearly stated that nonspecific androgen receptor inhibitors are not necessarily standard of care.
Judd Moul, MD: Correct.
Neeraj Agarwal, MD: Based on many more data, which were presented from 1988 to 2007, before these novel agents came up, I think the standard of care was not combining androgen deprivation therapy with these nonspecific androgen receptor blockers.
Judd Moul, MD: You’re absolutely right. Early in my career, I can remember in the 1990s—because we were all influenced by the New England Journal of Medicine and the flutamide trial being positive—I grew up in my training using flutamide or CAB [combined androgen blockade], and then Mario Eisenberger, MD’s, data with orchiectomy and flutamide was a negative trial, so it tailed off. Until the last couple of years, I was hardly ever using something like bicalutamide. I kind of abandoned CAB. And now, all of a sudden, it’s back in a big way.