mHSPC Regimens Are Distinguished by Drug Interactions and Disease Volume

Ganesh V. Raj, MD, PhD

Professor of Urology and Pharmacology

UT Southwestern Medical Center

Dallas, TX30

Targeted Oncology: Could you highlight practical considerations for the androgen receptor pathway inhibitor (ARPI) drugs used in patients with metastatic hormone-sensitive prostate cancer (mHSPC)?

Ganesh Raj, MD: For abiraterone [Zytiga] plus prednisone…the warnings for this, one important thing we talk about is avoid combination with radium-223 [Xofigo], and also the mineralocorticoid excess, which you deal with by titrating the prednisone. For apalutamide [Erleada] and enzalutamide [Xtandi], you worry about seizures, because both cross the blood-brain barrier. For darolutamide [Nubeqa], one of the new warnings that has come up is ischemic heart disease. Even though it does not cross the blood-brain barrier, almost all the patients in the ARAMIS [NCT02200614] and the ARANOTE [NCT04736199] studies were excluded for the same reasons as [the trials of] apalutamide and enzalutamide. If they had a prior history of seizure, if they had a brain tumor or any seizure medications, then they were excluded from these studies, so we don't know what the darolutamide seizure [risk is]. If you if you have a patient who has seizures, can you put them on darolutamide?

In terms of the most common adverse events [AEs] for all of these drugs, fatigue is the main one, except for darolutamide, where fatigue does not seem to be a big part of it [although] we do see it. But decreased appetite, hemorrhage and [other AE are seen]; all of them have the same or very similar AE profile. The key thing with enzalutamide is that the fatigue is probably more profound than with any of the other drugs.

What should physicians know about the drug-drug interactions with these agents?

For drug-drug potential [interactions, most oncologists] know that with abiraterone to avoid strong CYP3A4 inducers, and for the others, they have similar recommendations to avoid them.^1,2

[Data were presented at the 2024 European Society for Medical Oncology Annual Congress] on the drug-drug interaction potential with different drugs and the number of the likelihood of having drug-drug interactions.² These are the 4 different drugs, and abiraterone and prednisone has the lowest drug-drug interaction profile. There are very few things [with severe interactions]. Enzalutamide, apalutamide, and darolutamide have some degree of drug-drug interactions that you have to worry about. They tested drug-drug interaction with each one of 980 commonly used drugs. The ones that have the greatest degree of drug-drug interactions, almost identical, because these 2 drugs are [similar], are enzalutamide and apalutamide. Darolutamide and abiraterone have a much lower [number of relevant or severe interactions].

What are your takeaways from the different trial outcomes for these drugs in combination with androgen deprivation therapy (ADT) in mHSPC?

[We have data from] each one of those trials for [abiraterone], enzalutamide, apalutamide, and darolutamide [including] the ARASENS [NCT02799602] and the ARANOTE trials. Comparing all of them, we can look at the overall HR for each one of them, and for low-volume disease vs high volume. The overall survival for high-volume disease for LATITUDE [NCT01715285], which is the abiraterone plus ADT, is 0.62, and then the most recent one, ARANOTE, is 0.8.^3,4 They had slightly different patient populations, but still the HRs were 0.62 and 0.8. The HR for low volume goes from anywhere from 0.5 [for ENZAMET (NCT02446405) and TITAN (NCT02489318)] to 0.9 [for ARANOTE]. There were different numbers, but overall, the HRs for all of these metastatic combinations favor using either enzalutamide or apalutamide, and these 2 are virtually identical.³ For the ENZAMET and the TITAN studies, these numbers virtually overlap, and the graphs virtually overlap perfectly. These were the ones that were most commonly used. The abiraterone is not too bad, and darolutamide is the newest one. The [ARANOTE] data are a little immature...but that is where it is right now.

Disclosure: Raj previously disclosed serving or having served in an advisory role to Bayer, Johnson and Johnson, Myovant, EtiraRx, Amgen, Pfizer, and Astellas.

_REFERENCES:

_{1. Bernard A, Vaccaro N, Acharya M, et al. Impact on abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin. Clin Pharmacol Drug Dev. 2015;4(1):63-73. doi:10.1002/cpdd.132}

_{2. Mehra N. Invited discussant 1595MO, LBA68 and LBA69. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. https://tinyurl.com/yudd74mx}

_{3. Paolieri F, Sammarco E, Ferrari M, et al. Front-line therapeutic strategy in metastatic hormone sensitive prostate cancer: an updated therapeutic algorithm. Clin Genitourin Cancer. 2024;22(4):102096. doi:10.1016/j.clgc.2024.102096}

_{4. Saad F, Vjaters E, Shore ND, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. Ann Oncol. 2024;35(suppl 2):S1257-S1258. doi:10.1016/j.annonc.2024.08.2311}