Androgen Receptor Inhibition in CRPC
During a live virtual event, Evan Yu, MD, discussed the choice of novel hormonal agent for a patient with nonmetastatic castration-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. 3 months later, he had a robotically assisted radical prostatectomy and extended lymph node dissection. 6 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 status of 0. In October 2020, the patient’s PSA was 3.81 ng/mL.
What is your recommendation for next-line of therapy in this patient with nonmetastatic castration-resistant prostate cancer?
EVAN YU, MD: Why would you reach for a first-generation antiandrogen?
MEHRDAD JAFARI, MD: I did pick a first-generation antiandrogen, and the reason for that is mainly pragmatic reasons.
In this nonmetastatic recurrent disease, you have a drug that is effective, it is inexpensive, and it has hardly any adverse events [AEs]. So, I tend to use that in these settings, and I [have success] with it for a year or 2. And then once they [progress], I go to the next generation, mainly because of the cost.
YU: So, you would use something like bicalutamide [Casodex] due to the [low] cost and not having a lot of AEs?
A decision to add a novel hormonal agent was made. Which therapy would you most likely recommend?
YU: Which [novel hormonal agent] one would you select? Dr Jafari, let us say you used bicalutamide already and the PSA is still rising through [the treatment period], and you restage the patient. Still no metastases on CT or bone scan. Would you pick abiraterone [Zytiga], apalutamide [Erleada], darolutamide [Nubeqa], or enzalutamide [Xtandi] for this patient?
MANOJ AGARWAL, MD: I picked apalutamide because that is the first one to get approved for this specific indication of nonmetastatic castrate-resistant prostate cancer [nmCRPC].1 [I have] experience since I have been using it for the past year and more.
XINGWEI SUI, MD: I picked enzalutamide because I am familiar with it. That is the only reason.
YU: [Dr Agarwal’s reason] was that apalutamide was first to be approved in this setting…and enzalutamide was the first to be approved for metastatic CRPC, post-chemotherapy, and then pre-chemotherapy.2
ZHAO: I prefer darolutamide for a slightly better tolerability, and fewer interactions between this drug and others.
RAFEE TALUKDER, MD: I chose enzalutamide. I was between darolutamide and enzalutamide. Enzalutamide was more tolerable, and I have seen it more.
JAFARI: [I chose abiraterone for] similar reasons to [Dr Sui]. I am familiar with the abiraterone in the metastatic setting. And I am familiar with the AE profile, so I think I can manage them.
RISA WONG, MD: [The patient] has a seizure history.
YU: Yes. Does that affect your choices, Dr Wong?
WONG: I do not have any clinical experience with it causing seizures, but supposedly enzalutamide can lower the seizure threshold.3
YU: Yes, it is not high. It is [around] 0.6% to 0.9% in their early studies.4 Then subsequent earlier-stage studies are only 0.1%.5 But again, those trials excluded patients with a seizure history, and this patient already has a seizure disorder. Did you pick abiraterone, then?
WONG: I picked darolutamide because although they were not directly compared, it seemed to have the lowest rate of AEs compared with placebo.
YU: Darolutamide has a different biochemical structure than enzalutamide or apalutamide, and there are data to show that there is less crossing in the blood-brain barrier with darolutamide.6 So, the interesting thing is that the darolutamide clinical trials did not exclude patients with seizure history or seizure risk.7 It is the only agent that does not have a contraindication [or warning] for patients with seizures.
Now, abiraterone does not have any issue with seizures either, but it is not an androgen receptor antagonist. Although there are great phase 2 data, there has not been a randomized phase 3 trial with abiraterone in this setting.
So I think you hit the nail on the head there. If you are looking for FDA-approved answers for a patient with a history of seizures, darolutamide would be the best agent for this patient.
WONG: So, [the SPARTAN trial (NCT01946204) of] apalutamide also excluded patients with seizure history?
YU: Yes. Enzalutamide and apalutamide were created in the same lab. There is just a small change in the nitrogen side chain. So, they are essentially almost the same biochemical structure.
Abiraterone is not approved for treatment of nmCRPC. It is apalutamide, darolutamide, and enzalutamide [that are approved by the FDA].1,2,8
For abiraterone, there is only the phase 2 [IMAAGEN] study [NCT01314118]. The data looked great. If they ran a phase 3 study, it probably would work as well. It is just that abiraterone went generic, so nobody was going to back a phase 3 study in this situation.
CASE SUMMARY (continued):
After shared decision-making, darolutamide was initiated.
YU: What if the PSA doubling was not 8 months, but was 15 months? Does that change your decision making at all?
SUI: Yes, I think that makes difference if the doubling time is 6 months, 8 months, or 12 months, it makes a difference. If it were 15 months, I would think about it. If, for example, the PSA went from 1 ng/mL to 2 ng/mL, with a doubling time of 15 months, I may not change the regimen.
YU: You might just watch them for a while. Alright, that sounds good. Dr Shao, what would you do if the PSA doubling time was 15 months here?
SPENCER SHAO, MD: [There are] 2 choices. Either we watch for a while, or we can continue the hormone that he is [receiving] right now.
YU: Dr Sun, would you treat this patient, or would you observe, still just on ADT?
AMANDA SUN, MD: I would just continue the monotherapy. I wouldn't add another agent in this situation. Fifteen months doubling time can be monitored. Once the doubling time shortens you can initiate at that point.
YU: The most recent National Comprehensive Cancer Network guidelines [recommend that patients with] nmCRPC with rising PSA should continue ADT with leuprolide [Lupron]. And they break it down based on whether the PSA doubling time is less than or equal to 10 months, or greater than 10 months.9
If the PSA doubling time is greater than 10 months, then observation is preferred, or other, secondary hormone therapy like bicalutamide. If it is less than or equal to 10 months, the preferred category 1 recommendations are apalutamide, darolutamide, or enzalutamide. But they say you can also use other secondary hormonal therapies as well.
1. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. FDA. Published February 14, 2018. Accessed February 15, 2022. https://bit.ly/3LGHvgc
2. FDA approves enzalutamide for castration-resistant prostate cancer. FDA. Published July 13, 2018. Accessed February 16, 2022. https://bit.ly/3GOoZPn
3. Enzalutamide (Xtandi). Prescribing information. Pfizer; 2020. Accessed February 16, 2022. https://bit.ly/367gOAP
4. Slovin S, Clark W, Carles J, et al. Seizure rates in enzalutamide-treated men with metastatic castration-resistant prostate cancer and risk of seizure: the UPWARD study. JAMA Oncol. 2018;4(5):702–706. doi:10.1001/jamaoncol.2017.3361
5. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892
6. Crawford ED, Stanton W, Mandair D. Darolutamide: an evidenced-based review of its efficacy and safety in the treatment of prostate cancer. Cancer Manag Res. 2020;12:5667-5676. Published 2020 Jul 13. doi:10.2147/CMAR.S227583
7. Darolutamide (Nubeqa). Prescribing information. Orion Pharma, 2019. Accessed February 16, 2022. https://bit.ly/3sMSpbC
8. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. FDA. Published July 30, 2019. Accessed February 15, 2022. https://bit.ly/3HVMM17
9. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 3.2022. Accessed February 16, 2022. https://bit.ly/3GU39tI