Androgen Receptor Inhibition in CRPC - Episode 7

Part 2: Later-Line Therapy in nmCRPC Post Androgen Deprivation Therapy

Tanya Dorff, MD, asks the participants of a roundtable discussion what they would recommend as next-line therapy for a patient with nonmetastatic castration-resistant prostate cancer.

CASE SUMMARY

A 57-year-old Black man presented with an elevated prostate-specific antigen (PSA) level. He had a history of seizures managed on medication and a family history of cancer (mother and sister had breast cancer and brother had pancreatic cancer). Bone scan was negative for metastases. He underwent a radical prostatectomy and extended lymph node dissection. Adjuvant radiotherapy was recommended but refused. Androgen deprivation therapy (ADT) was initiated. After more than a year the patient re-presented with a PSA doubling time of 8.6 months and was still nonmetastatic.

What is your recommendation for next line of therapy in this patient with nonmetastatic castration-resistant prostate cancer?

SARMEN SARKISSIAN, MD: You can probably just knock out taxane chemotherapy because I think there are more than enough survival data and time-to-chemotherapy data to really put that in our back pockets for [issues] like visceral crisis.

TANYA DORFF, MD: Most people favor adding a novel hormonal therapy: enzalutamide [Xtandi], apalutamide [Erleada], or darolutamide [Nubeqa]. To me, this feels like a big moment for the patient because often they’ve been on intermittent hormone therapy and now you’re telling them it’s going to be lifelong and you’re going to add a second drug.

How much does quality of life come into play with your discussions with these patients at this juncture? Are patients more worried about their cancer and their survival, or do they really worry about the adverse events [AEs]?

SANDY LIU, MD: I think it’s both for my patients. They’re monitoring their PSAs very closely and worried about developing metastases, but they also care about their quality of life on hormone therapy, whether it’s hot flashes, fatigue, fractures, or muscle loss.

EDWARD ALEXSON, MD: I think quality-of-life issues always matter, especially the fatigue and muscle loss, [considering that] this patient is only in his 50s.

LIU: For my patients, financial [concerns are also important].

DORFF: That’s a great point. Cost might influence our selection or a go/no-go decision.

SAM YEH, MD: For my patients, it’s the leuprorelin that they are most concerned about. A lot of them dread having that medication: the hot flashes, the fatigue, the muscle problems, and [diminished] libido….They’re more OK with the second-generation enzalutamide [because] the AEs are not too bad. I dose them based on testosterone level. If their testosterone levels start to rise, then I’ll give them a dose. But if [the level stays] low, less than 50, then I might just watch it.

ARATI CHAND, MD: I do the same thing with the testosterone level. It’s interesting; even months after stopping the leuprorelin, some of these men don’t regain testosterone levels above 50 ng/dL.

SARKISSIAN: Recently I had a patient with anxiety.…He could not commit to leuprorelin, but I was able to give him apalutamide. The apalutamide dropped his PSA by almost 3 orders of magnitude just by itself, without ADT and the menopausal AEs. Most studies have ADT running in the background. I don’t know how many studies there are with novel agents without ADT. It might be an interesting angle to take.

DORFF: Enzalutamide monotherapy…can be effective. [This patient is] different because his cancer is castration resistant. But I do think there need to be more studies of noncastration approaches, and maybe monotherapy with these newer agents could be quite effective. But it’ll take a while for a really definitive study to happen. But I will say I have done it on some patients who have refused leuprorelin. It does work. Probably not as well.

When patients are on leuprorelin and they’re struggling with all these AEs and they say, “You’re going to add a pill that’s going to be even more intensive,” I usually counsel them that I don’t see a significant increase in AEs, generally speaking, with [enzalutamide, apalutamide, or darolutamide]. There can be more fatigue. Do you see a lot of added AEs when you add one of these agents on top of the leuprorelin?

CHAND: Rarely. I recently had a patient on enzalutamide who refused to take the medication because he was having a lot of nausea, vomiting, and fatigue; he could barely get out of bed. I’ve had so many patients on enzalutamide and they’ve never complained of anything. But we switched him to apalutamide and he seems to be tolerating it better. I think there is some difference between the agents.

VEENA CHARU, MD: I see the same thing with enzalutamide. They have more fatigue.

LIU: I think my older patients have a little bit more fatigue with enzalutamide. But otherwise, it’s well tolerated.

DAVID SHIN, MD: Do you ever try antiandrogen withdrawal?

DORFF: Sure. There was a study where they switched out the prednisone for dexamethasone and saw a lot of patients’ PSAs decline. I’ve experienced it in my own patients. It’s interesting that the switch can make such a difference.

YEH: How do you switch from prednisone to dexamethasone? What’s the dose?

DORFF: The dose is 0.5 [mg daily]. Some of my colleagues have said they’ve tried it and it didn’t work, but I’ve done it in a handful of patients and I’ve had a few where it really worked.

LIU: Same here. Yes, it did drop.

DORFF: These are old-school maneuvers [from] before we had lots of lines of therapy. We would do antiandrogen withdrawal; we would switch out the steroid. A lot of these patients’ cancers progress slowly, and you have that luxury. Obviously, some cancers progress rapidly and you need to just move on.