Androgen Receptor Inhibition in CRPC

Part 2: Concerns When Selecting a Novel Hormonal Agent for CRPC

During a live virtual event, Alicia Morgans, MD, MPH, discussed the choice of novel hormonal agents to combine with androgen-deprivation therapy in nonmetastatic castrate-resistant prostate cancer.


In October 2016, a 57-year-old black man was referred to the urology department with a PSA (prostate-specific antigen) of 6.8 ng/mL. His medical history included seizures that were controlled with oxcarbazepine. His mother and sister had a history of breast cancer, and his brother had a history of pancreatic cancer. A multiparametric MRI scan showed a 58 cc index lesion to his left prostate zone, and prostate imaging reporting and data system showed it to be 4/5, 1.8 cm. Three months later, he had a robotically assisted radical prostatectomy and extended lymph node dissection. Six weeks post operation, the patient had a PSA of 0.15 ng/mL and baseline serum testosterone of 420 ng/mL.

Androgen deprivation therapy (ADT) was initiated with leuprolide depot at 45 mg. The patient returned in August 2019. His PSA doubling time (PSA-DT) was 8.6 months with a PSA of 1.2 ng/mL. In October 2019 he was restaged, and bone scans showed he was negative for metastatic disease with an ECOG performance score of 0. In October 2020, the patient’s PSA was 3.81 ng/mL.

A decision to add a novel hormonal agent was made. Which therapy would you most likely recommend?

ZUHAIR GHANEM, MD: Well, one of the options [should] be observation, or to continue to watch, because I think it’s a discussion with the patient at this point. I think, from the case, I get the feeling that the patient has a good performance status. He had the seizures, so one of the options for the patient is watchful waiting and observation. I know the PSA-DT was [nearly] 9 or 10 months, so that’s the thing we have to discuss with him.

The current standard is to do the novel hormonal therapies. I am more familiar with apalutamide [Erleada] than the rest. Abiraterone [Zytiga)] is not an option in this case, because it is not metastatic disease—the scans were negative. The patient had a seizure, so enzalutamide [Xtandi] is not a good option, either. So, probably if I were treating the patient, it would be apalutamide as the standard, more familiar option for me.

ALICIA MORGANS, MD, MPH: It sounds like this patient, essentially, qualifies as nonmetastatic castrate-resistant prostate cancer [nmCRPC], and you went through the different treatment options, and why you would choose apalutamide. But you acknowledged that the patient’s actually doing well, has a good performance status, and then it’s a conversation about whether or not you want to put the patient through further treatment at this time; whether the patient wants to go through further treatment at this time, and we should engage the patient in that conversation.

AJAY KANDRA, MD: I think the patient having seizures should also be one of the considerations, because some of [the hormonal agents] can cause central nervous system [CNS] issues, especially enzalutamide. I’m not so much familiar if apalutamide has that [adverse event]. I think the newer generation ones seem to have fewer CNS issues. Abiraterone does not have that issue, but it does have other things: fluid retention, cardiac [issues]. So, I think we need to look at all these [concerns] when we are looking at the patient.

I believe there are data for using these agents in PSA progression, but not as much as the type of data you see in patients with metastatic CRPC. This is still a biochemical progression only.

MORGANS: There is CNS penetration with enzalutamide, and also with apalutamide, believe it or not. Patients with a seizure history, or a seizure threshold that was lowered, were not eligible to participate in the trials, particularly because enzalutamide, in prior trials, had a seizure signal just like you mentioned, and apalutamide had a slight signal as well. Darolutamide [Nubeqa] was the only drug that was tested and allowed patients who had a seizure history into the trial. So, the seizure history, I think, would compel me to use darolutamide.

To your point, this is a biochemical recurrence. This is a PSA rise in the absence of radiographic evidence of metastatic disease by our traditional, old-fashioned imaging strategies, bone scan and CTs. That is the definition of nmCRPC. Importantly, in the phase 3 trials that led to the approval of these 3 drugs, about 98% of patients would have a positive lesion on the PET scan. But despite that positive lesion, if you added apalutamide, darolutamide, or enzalutamide to their ADT, they had about a 2-year prolongation of time to metastatic disease, as compared with ADT alone.1 They even had a survival advantage as compared with ADT alone. So, it’s phase 3, level 1 evidence, and it’s pretty compelling.

This patient got darolutamide because he had a seizure history, and to Dr Kandra’s point, that’s really important, and that was the only study that allowed in patients who had a seizure history.


1. Swami U, Agarwal N. Improvement in overall survival with Apalutamide, Darolutamide and Enzalutamide in patients with non-metastatic castration-resistant prostate cancer. Cancer Treat Res Commun. 2020;25:100205. doi:10.1016/j.ctarc.2020.100205