Androgen Receptor Inhibition in CRPC
In a roundtable discussion with multiple participants, Alicia K. Morgans, MD, MPH, reviews the options for a patient with castration-resistant prostate cancer who progressed on front-line therapy.
A 75-year-old man presented with intermittent right hip pain, but his physical exam was unremarkable and he had a an ECOG performance score of 1. Clinical work-up of the patient showed he had a PSA (prostate-specific antigen) of 32.6 ng/ mL and his trans rectal ultrasound guided biopsy Gleason score was 4+4 in the 4 grade group. He had a negative bone and abdominal/pelvic CT scan and was diagnosed with stage T2N0MO prostate cancer. External beam radiation therapy and androgen deprivation therapy (ADT) were initiated and planned for 18 months. Six months after initiation of therapy he had undetectable PSA, was asymptomatic, and his testosterone was at castrate level.
Six months after this, he complained of increasing hip pain and urinary frequency. He had a PSA level of 29.4 ng/mL and testosterone level of 10 ng/dL. Another bone scan showed evidence of 2 osteoblastic lesions in his right hip at 0.8 cm and 1.1 cm. An abdominal/pelvic CT scan showed a 2.1-cm left pelvic lymphadenopathy and he is now considered metastatic and castration resistant.
A decision to add a novel hormonal agent was made. Which therapy would you most likely recommend?
EVAN LANG, MD: I have been using apalutamide [Erleada] and I feel very comfortable in using it. And, if I remember correctly, it’s just 2 to 3 years of survival benefit by adding apalutamide.
ALICIA K. MORGANS, MD, MPH: I think that the years of benefit was not defined. The metastasis-free survival was about 2 years longer for apalutamide, enzalutamide [Xtandi], and darolutamide [Nubeqa]...I don’t know that we’ve reached the overall survival final end points. But we’ll look at that data, too, but all 3 of these agents are also associated with a similar survival benefit, exactly as you’ve said.
SHYAMAL BASTOLA, MD: I think a lot of it is familiarity. Although, it sounds like in the cross-trial you can talk about tolerance, maybe some agents are more tolerable than the others. I haven’t really been paying a whole lot of attention to that. I have been using a lot of enzalutamide, just because I have a lot of experience with it in other settings. But it does seem like I may have to start thinking of others, because there are some data suggesting better tolerance. Efficacy-wise, it seems similar.
We wish we had a head-to-head trial, which we’re probably never going to have. We’ll have to be stuck with figuring out what works best when we have these agents, especially when working in the community, and we are treating multiple cancers.
We do like to have 1 go-to agent that we can get more experience and stick with it. That’s where it becomes hard sometimes.
MORGANS: I think those are incredibly valid points. It’s not just in the community that we like to have a go-to agent. I like a go-to agent, too.
MICHAEL NEMUNAITIS, MD: I’ve used apalutamide and enzalutamide multiple times. I’ve never used darolutamide. Is there a certain situation where you would use that 1 in particular or not particularly?
MORGANS: That 1 is the only trial that included patients who had a seizure history in the randomized trial. It’s the only 1 that doesn’t seem to cross the blood-brain barrier, so patients who had a seizure history or a low seizure threshold because of other drugs that they might be on, they were in the trial. There was no real risk of seizures, so to me, that’s compelling for that population. The other thing that is interesting is that the drug is shaped differently than the other 2. Apalutamide and enzalutamide are very close relatives of each other and darolutamide is a little bit shaped differently, so it doesn’t cross the blood-brain barrier in the same way and doesn’t seem to have the same drug-drug interactions that we can see, particularly with enzalutamide.
I use all of these agents. Enzalutamide can have some interactions with certain cardiovascular medicines and anticoagulants that can be frustrating, because then I have to call the cardiologist and say, “Can you change this medication, please?” Darolutamide has fewer drug-drug interactions, so I find that easy to use. None of these have been compared head to head to the points that have been made. It’s hard to really say that this one’s better than that one. But [with] some of the patient-reported outcomes there seemed to be a little less fatigue, perhaps, with darolutamide, so maybe a little bit better tolerability. But again, they’re not compared head to head, so it’s really hard to say.
TAREK SABAGH, MD: I used the apalutamide for a patient and for some reason he didn’t tolerate it. He was complaining of abdominal distension, upset stomach. I don’t know why. This was 1 experience, which somehow discouraged me and made me go back to the enzalutamide, which I’m more familiar with from before in the metastatic setting.
ARUN KUMAR, MD: I think you can use any of the 3, but it depends on the co-pay and the cost, I think.
MORGANS: A lot of times we try to make our decisions, but there are situations where insurance says, yes, I appreciate that, but unless you have a compelling reason, this is the 1 I’m going to pay for. We sometimes find ourselves in that situation.
In this case, this patient started darolutamide.