ARANOTE Trial Aligns With Prior ARPI Plus ADT Studies in mHSPC

Ganesh V. Raj, MD, PhD

Professor of Urology and Pharmacology

UT Southwestern Medical Center

Dallas, TX

Targeted Oncology: What are the treatment options available for a patient with low-volume metastatic hormone-sensitive prostate cancer (HSPC)?

Ganesh V. Raj, MD: The androgen deprivation therapy [ADT] and androgen receptor pathway inhibitor [ARPI] combination for metastatic HSPC started off initially with the LATITUDE study [NCT01715285] and the ENZAMET study [NCT02446405], leading to approval of abiraterone [Zytiga] first in 2018, then approval of enzalutamide [Xtandi] in 2019, then apalutamide [Erleada], and most recently, the ARANOTE study [NCT04736199] came out…that was the 2024 data showing [benefit] of darolutamide [Nubeqa] for metastatic HSPC.

If you look at the 4 most common trials that define these, ENZAMET, [LATITUDE], TITAN [NCT02489318], and ARANOTE studies…the overall survival [OS] HR was very similar for all of them, somewhere between 0.6 to 0.81.^1-4 The difference is in the study population, and OS is relatively similar. For each one of these, the OS is statistically significant, except [ARANOTE], where it crosses 1. In ARANOTE alone, the OS was not statistically significant. The median radiographic progression-free survival [rPFS] was significant in every single one of them. The ARANOTE study is the most recent study. All these studies together show a similar OS trend.

Could you describe the outcomes of the ARANOTE trial in more detail?

The ARANOTE study is a phase 3 trial… I [was surprised] they enrolled patients to placebo plus ADT vs darolutamide plus ADT, given the fact that all these [ARPIs] were FDA approved, but they got this trial approved and enrolled. They had a 2:1 ratio for enrollment, because you want to minimize the number of patients in the placebo arm. The primary outcome was rPFS, and then secondary outcomes were OS, time to PSA progression, and time to pain progression.

If you look at the baseline characteristics, we always look at the 2 groups and compare the groups and make sure the groups were similar.⁴ The overall proportion of patients in the darolutamide plus ADT arm vs a placebo plus ADT arm were relatively similar, except the proportion of patients here who were of African American ancestry was a little lower and Asian Americans was a little higher in the placebo arm compared with the darolutamide arm.

Overall, rPFS was very similar. If you look at the data, comparing it to ARCHES and TITAN and those studies, you see a very similar, almost superimposable rPFS, with a 2-year rPFS rate for darolutamide and ADT at 70% vs 52% for placebo plus ADT, giving an HR of 0.54 for rPFS [95% CI, 0.41-0.71; P < .0001], very similar to what you would see with enzalutamide, apalutamide, or abiraterone, with a very similar outcomes in terms of rPFS for darolutamide.

If you look at each subgroup, it doesn't matter whether the disease volume is high [HR, 0.60] or low [HR, 0.30]. For each of the subgroups, the HR favors giving darolutamide over placebo. The only time it didn't was in the higher age group, over 85 [HR, 0.51; 95% CI, 0.16-1.66]. It's not a huge number of patients, but that that population didn't meet the HR, which makes sense. Finally, patients who did not have visceral metastases, who had bone-only metastases, did well with the darolutamide [HR, 0.52; 95% CI, 0.39-0.69], but for patients with visceral metastases [the HR was 0.71; 95% CI, 0.35-1.41]. If you have visceral metastases, you want to think about more aggressive treatment, potentially adding a chemotherapy or something else.

How did darolutamide perform in terms of OS and other end points?

For secondary end points, OS crosses the line, so it did not achieve statistical significance [HR, 0.81; 95% CI, 0.59-1.12]. Part of that is the crossover design of the trial, and part of it is the lack of maturity of this trial. We think that as a trial becomes more mature, this HR for the OS will become significant. But if you look at the time to metastatic castration-resistant prostate cancer, time to prostate-specific antigen progression, time to rPFS, time to pain progression, and initiation of subsequent therapy, these lines overlap very well with the other studies for enzalutamide and apalutamide in terms of the secondary end points.

This work was just presented this year at the 2024 European Society for Medical Oncology Annual Congress, and the importance of the ARANOTE study and approval of darolutamide in this [setting] was one of the big findings.

What was notable about the tolerability of the ARANOTE trial regimen?

In terms of tolerability, 91% of patients had some degree of adverse events [AEs] with darolutamide plus ADT, but [the incidence of] grade 3 or 4 was only 30% vs 30% in placebo and ADT, mostly related to the ADT itself. The rates of grade 5 AEs were 4.7% and 5.4% [respectively]; the rate of serious AEs was no different from ADT; and for those leading to permanent discontinuation of drug, ADT alone was 9% and darolutamide was 6%, so this is not worse than ADT alone.

One of the most common AEs we always talk about is fatigue. ADT itself causes fatigue, [and the rate] is 8.1% with darolutamide plus ADT vs 5.6% with the placebo and ADT. Then if you look at falls, note that the bone fracture rate in the patients undergoing ADT plus darolutamide was a little higher.

Not all those patients were on bone protective agents. One of the key things we always talk about is no matter what agent you're on; you want to make sure that they are on some bone protective agents. This fracture risk is almost 2-fold higher with darolutamide plus ADT vs placebo plus ADT, which is important. The other trials didn't exactly look at that and didn't report that. [This trial] did, so they look worse. But this is something that is of importance, that the fracture rate is higher. They didn't mandate that they had to be on bone protective agents, but one of the things we recommend highly is all these patients on an androgen receptor pathway inhibitor go on bone protective agents. The rest of the complications are relatively similar in both arms.

_{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. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700. doi:10.1016/S1470-2045(19)30082-8}

_{2. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(4):323-334. doi:10.1016/S1470-2045(23)00063-3}

_{3. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488}

_{4. 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}