Rates of Drug Interactions Differentiate ARPIs for Treating mHSPC

With 4 approved androgen receptor pathway inhibitors (ARPIs) in use in combination with androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC), the differences in tolerability, quality of life, and other factors are of greater interest to oncologists. During a Community Case Forum event in Bridgewater, New Jersey, Cora N. Sternberg, MD, professor of medicine at Weill Cornell Medical College, looked at the ARANOTE trial (NCT04736199) of darolutamide (Nubeqa) plus ADT in this setting, then evaluated the most notable toxicities seen with one or more of these agents and studies of drug-drug interaction in older patients who commonly receive a number of other medications.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: How do you interpret the tolerability outcomes in the ARANOTE trial for mHSPC?

Cora N. Sternberg, MD: [In terms of] treatment-emergent adverse events [AEs], when you see something like this, you have to realize that in the darolutamide and ADT group, the median treatment duration was 24 months vs [17 months with] the placebo.^1,2 So they had a longer time to have AEs. The numbers look pretty much the same in terms of treatment-emergent AEs in both arms, even though they were on treatment for a longer time, and there’s not much difference here. The most common AEs are similar with darolutamide and ADT vs placebo and ADT. I don’t see much difference—maybe for falls, and bone fracture incidence is 4% vs 2.3%; that’s a big difference. Hypertension was 9.4% vs 9.5%; it was well tolerated. Skin rash was similar. People can get skin rash from any of these drugs, and [the rate] was similar to not getting it.

If we look at health-related quality of life, the time to pain progression favored darolutamide [HR, 0.72; 95% CI, 0.54-0.96].³ The Functional Assessment of Cancer Therapy-Prostate [FACT-P] total score, which was one of the exploratory end points, [showed] a difference of 5 months in favor of darolutamide [HR, 0.76; 95% CI, 0.61-0.94]. The FACT-P includes social and family well-being, functional well-being, and urinary symptoms.

The FDA approved darolutamide for mHSPC on June 3, [2025], so we now have this in our armamentarium, along with all the other drugs.⁴

How do you decide which of the ARPIs to use in patients with mHSPC?

For me, darolutamide is relatively new. I had more experience with enzalutamide [Xtandi]. I would try to balance patients with heart disease and not try to give them prednisone. In older patients, I would try not to give them enzalutamide because of the fractures and the falls. I personally have less experience with darolutamide, but the more patients who I see who are frail—I see them all the time—I think this is a drug that I’m going to use, and I use it more and more.

What stands out from the label warnings and most common AEs for ARPIs?

I was surprised when I saw [warnings for] embryo-fetal toxicity, because the majority of our patients are not having children. It’s not just in darolutamide, it’s in enzalutamide and all of them. Apalutamide [Erleada] has rash as one of the problems. With enzalutamide, we’ve discussed the [risk of] falling down. Darolutamide might also have some increased liver function tests, like abiraterone [Zytiga], and decreased neutrophils. They all have AEs, but aspirin has AEs as well.

How do you consider the drug-drug interaction issues with ARPIs?

They have drug-drug interaction potential, and probably the biggest offender of that is enzalutamide. They seem to have more tolerability issues combined with strong CYP3A4 inhibitors. Not that many drugs are CYP3A4 inhibitors that we use every day. If you look it up [or have] a specialty pharmacy, they’ll tell you about things like phenytoin [Dilantin] and alcohol. Darolutamide is weaker [interacting with CYP3A4 inhibitors].⁵

Talking about the potential of drug-drug interactions, [in patients] with prostate cancer, the number of comedications is more than 15 [in over 30% and] 85% of patients are at risk for some drug-drug interaction.⁶ From what I know, over 7 days, patients are on an average of 10 drugs. They’re saying too, if you look at the data from a database of 980 commonly used drugs—and they tested for the drug-drug interactions between ARPIs—abiraterone and darolutamide had less than enzalutamide and apalutamide.

_{DISCLOSURES: Sternberg previously reported consultancy/advisory fees from Bayer, MSD, Pfizer, Roche, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Genzyme, Foundation Medicine, Bristol Myers Squibb/Medarex, Gilead Sciences, and Janssen Oncology; and honoraria from Merck and Pfizer.}

_REFERENCES:

_{1. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798}

_{2. Saad F, Vjaters E, Shore N, 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}

_{3. Morgans AK, Haresh KP, Jievaltas M, et al. Health-related quality of life (HRQoL) outcomes with darolutamide in the phase 3 ARANOTE trial. J Clin Oncol. 2025;43(suppl 16):5004. doi:10.1200/JCO.2025.43.16_suppl.5004}

_{4. FDA approves darolutamide for metastatic castration-sensitive prostate cancer. FDA. June 3, 2025. Accessed November 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-metastatic-castration-sensitive-prostate-cancer}

_{5. 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}

_{6. Mehra N. Invited discussant 1595MO, LBA68 and LBA69. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain.}