Cusnir Explores Impact of ARANOTE Data on ARPI Plus ADT Use in mHSPC

Mike Cusnir, MD

Chief, Division of Hematology & Oncology

Codirector, Gastrointestinal Malignancies

Assistant Professor

Columbia University Division of Hematology/Oncology at Mount Sinai Medical Center

New York, NY

Peers & Perspectives in Oncology: What was learned from the recent phase 3 ARANOTE trial (NCT04736199) data?

CUSNIR: This study was presented this year just after the data cutoff…. It’s not [fully] mature yet. ARANOTE, which was the last study [of an androgen receptor pathway inhibitor (ARPI) plus androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC)], was a very simple 2:1 [randomization] study of single-agent [darolutamide (Nubeqa)] plus ADT vs placebo plus ADT. In my view, this is the last study we’re going to be able to conduct this way. The primary end point is radiological progression-free survival [rPFS] by central blinded review. Overall survival [OS] was a secondary end point, [along with] patient-reported outcomes and some other [outcomes]. There were well-distributed groups and high-volume disease for the patients. This is a group that, nowadays, nobody will randomly assign patients to ADT alone. Even on the visceral metastasis, 12% is not a small number, and not many had local therapy.¹

…There is a very heavy rPFS [difference] that was the primary end point [HR, 0.54; 95% CI, 0.41-0.71; P < .0001]. This is fully mature; it is not going to change, even though the data cutoff was recent. You would think the censored curves of all these patients… might end up swinging the [Kaplan-Meier] curve back down a bit. I think these curves are going to stay here.

[The rate of rPFS] at 24 months was 70% [for darolutamide vs 52.1% for placebo]. The darolutamide group did not reach the median [95% CI, not reached (NR)-NR], [whereas the placebo group] reached the median at 24 to 27 months, which is what we expect [median, 25.0 months; 95% CI, 19.0-NR]. This is right on the line of what you would expect from the rPFS, but median follow-up is already passing what will be the median follow-up of the placebo group, and the median follow-up of this group is still 20% above. I think it’s safe to say that we’re going to see [rPFS superiority] all the time.

This is something I found quite interesting…you would have expected patients with high-volume disease to perform even better. It was highly significant [HR, 0.60; 95% CI, 0.44-0.80], but you would expect that the doublet would have been much more. There was a wider CI in the low volume [HR, 0.30; 95% CI, 0.15-0.60], but the high-volume group of patients still met the end point. I would have guessed this to be completely opposite. Don’t forget that [high volume] was 70% of the patients and [low volume] is only 30%. You wouldn’t expect that 30% of the patients were going to have a wider CI and still meet significance in adding that 30% of patients, which is amazing. Why is that happening? In a 2:1 randomization of 131 patients [with low-volume disease receiving darolutamide], only 15 patients had rPFS events [vs 19 of 66 patients who received placebo].

It’s amazing that the group of patients was 130 and they’re still meeting [significance]. But with high volume, half of the patients [receiving] placebo had events—75 of 150—vs one-third of the patients [113 of 315 receiving darolutamide]. For those with visceral metastasis, it’s crossing [the CI], so is it that worthwhile for visceral metastasis? That’s where we are now.

I always look at the [older] population [I treat] here in Miami, [Florida], and the [older] population was minute—[18 in the darolutamide group and 10 in the placebo group who were aged 85 years or older]. I think we need to get much stronger in [enrolling these patients].

OS was a secondary end point, [but] it was negative. The OS did cross the CI, and it was not significant as of the [immature] cutoff date [HR, 0.81; 95% CI, 0.59-1.12]. Could it become significant later on? I don’t know.

The secondary end points, such as the time to metastatic castration-resistant prostate cancer, PSA progression, and pain progression, separated [in favor of darolutamide] much more [Table¹].

How did darolutamide perform in terms of safety and tolerability?

The placebo group had a higher treatment-emergent AE rate that prompted discontinuation of the study drug [6.1% for darolutamide vs 9.0% for placebo]. [It appeared that placebo] was more toxic than the drug. Grade 5 toxicity, meaning lethal toxicity—even though it was low—[was similar]. The difference is going to be in the drug-drug interactions….

I think we are used to [AEs because] we use a lot of enzalutamide [Xtandi], and the dizziness and some of the different AEs tend to come to mind. [Bone fractures and falls] are interesting, as they’re not that high [with darolutamide]. Vasomotor events are a little higher but nothing major, and the fatigue is lower than the placebo. This is something that might end up [mattering] because when you have a drug that is the same but less toxic, that does bring it back to the table.

What is the significance of drug-drug interactions in the use of ARPIs?

Here in Florida, almost all my patients are on hypertensive medications, anticoagulants—you name it—and the interaction of those drugs is what is going to be big because of the different toxicities. There are warnings on all of them. They still have the warnings… [with abiraterone (Zytiga)]. I have been decreasing the prednisone even more. I even remember one of the earlier studies that used 4 mg of dexamethasone instead of 5 or 10 mg of prednisone. I don’t think the steroids are doing too much, but it still is a pain, and the patients don’t like them, which is one of the issues. Avoiding combination of abiraterone with radium-223 [Xofigo] is on the precautions and the label. It increases the risk of fractures, but we’re combining [radium-223] with chemotherapy.

CYP3A4 is the substrate of abiraterone and darolutamide, whereas [enzalutamide and apalutamide (Erleada)] have more major levels of CYP2C8. The way they interact is probably where we end up getting [darolutamide] approved in the front line. Even if the data do not convince [the FDA] because of lack of OS, it gives the option of a medication that does not interact that much with anticoagulants and antihypertensives…. It still is a CYP3A4 inhibitor. Don’t [even] use it with St John’s wort, [which is] a CYP3A4 inducer.

The drug-drug interactions have been looked at in older men, [which] is something quite elegant. [A prior publication] looked at the database and then tested it, and 85% of the patients will be at risk with enzalutamide…of drug-drug interactions with the most common drugs that are used by the older population,² whereas the patients [receiving] darolutamide have [no or minimal interaction with 855 of 980 common drugs vs 613 of 980 with enzalutamide and 570 of 980 with apalutamide].³ So, keep using your assistants and keep believing them when they tell you there is a drug-drug interaction.

_REFERENCES

_{1. 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}

_{2. Benoist GE, van Oort IM, Smeenk S, et al. Drug-drug interaction potential in men treated with enzalutamide: mind the gap. sBr J Clin Pharmacol. 2018;84(1):122-129. doi:10.1111/bcp.13425}

_{3. Mehra N. Invited discussant 1595MO, LBA68 and LBA69. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. https://tinyurl.com/yudd74mx}