Considering the Evolution of ARPI Combination Therapy in mHSPC

Combinations of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) are the accepted treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC). While moderating a Community Case Forum event in Bridgewater, New Jersey, Cora N. Sternberg, MD, professor of medicine at Weill Cornell Medical College, reflected on the development of these regimens and discussed the trial outcomes of the most recent presentation of the ARANOTE trial (NCT04736199) that established the role of the ARPI darolutamide (Nubeqa) plus ADT in this setting.

With this regimen achieving FDA approval, there are now 4 approved ARPIs in use, though Sternberg noted there are still disparities limiting the use of standard of care. Evaluating the differences in trial design, location of enrollment, and secondary end points have provided additional ways to distinguish between the trials in this setting.

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Targeted Oncology: What do the NCCN guidelines recommend for patients with mHSPC?

Cora N. Sternberg, MD: The NCCN guidelines…were updated to [version 1] of 2026.¹ If we talk about patients with synchronous low-volume or oligometastatic disease, ADT is preferred in combination with abiraterone [Zytiga], apalutamide [Erleada], enzalutamide [Xtandi], or darolutamide. They say ADT with docetaxel is for low-volume disease only; if patients have metachronous disease, it comes later on. ADT with one of the [ARPIs] is preferred. You need to use what you’re most familiar with, using which you think has the least toxicity as well.

If you look at the ADT and ARPI combinations for mHSPC, the timeline has been amazing. I’ve been working for a very long time. In the beginning, in 2004 there was a preplenary section with Ian Tannock [MD, PhD] speaking about docetaxel chemotherapy…and that’s what we had for a very long time. [The current treatment landscape] starts with docetaxel plus ADT. With all these different studies, the majority of them are ADT and ARPI. Then we get to the more recent ARASENS trial [NCT02799602] and the PEACE-1 trial [NCT01957436] with the triplet therapies. Most recently, we heard the ARANOTE at ASCO with darolutamide and ADT, and that also has been approved.

…All of those different trials [began] with LATITUDE [NCT01715285], which is the French trial with abiraterone and prednisone and STAMPEDE [NCT00268476], which is the English trial with abiraterone and prednisone vs ADT alone. ENZAMET [NCT02446405] was an Australian trial that was ADT and enzalutamide. The ARCHES trial [NCT02677896] was an American trial of ADT and enzalutamide. The TITAN trial [NCT02489318] was a mostly American trial of ADT and apalutamide. Most recently, the ADT and darolutamide [data were] presented by Fred Saad, [MD] from Montreal. So, we have quite a number of trials showing that by adding an ARPI to ADT, that we can improve survival and improve radiographic progression-free survival [rPFS] in patients across the line.

In both the ARCHES trial and the ARANOTE trial, rPFS was the primary end point. There’s not enough follow-up for sure to have overall survival [OS]. If you look at the median rPFS in all these trials, it’s always difficult to compare among trials with different patients. I don’t think that there are huge differences. They’re all good; they all work. In terms of OS, some of them are not yet reached because they haven’t been around [long]…. With high volume and low volume, patients benefit from a doublet therapy in all of the trials.

Could you describe what stood out about the ARANOTE trial design?

This is the ARANOTE trial that was presented by Fred Saad from Montreal at the [2024] American Society of Clinical Oncology Annual Meeting.^2,3 There were 669 patients in this international trial. It was randomized 2:1 to receive either darolutamide and ADT or placebo and ADT.

All of these trials are like that—we know now that ADT alone couldn’t [be used as a comparator] but if you look in the community…in the United States, many patients are treated by urologists [and] many patients are treated by [oncologists] in practice with multiple specialties, and only 50% of people actually get a doublet treatment here. That’s not even to say in Europe and in other places where they don’t even have access or specialty pharmacy so they can’t afford it. Here in this country, that’s what’s happening.

This trial is for patients with confirmed prostate cancer with or without a first-generation antiandrogen, no prior second-generation ARPI. They could have had a little bit of bicalutamide at the beginning. They were randomized 2:1 and the primary end point here was rPFS by blinded independent central review. They stratified patients by visceral metastases and prior local therapy.

What were the baseline patient characteristics in this trial?

What was highlighted is that in this trial there were [over] 30% Asian patients and 10% Black patients, which was not happening on the other trials. In the Australian trial they were practically all White patients. That’s something interesting about this trial. They’ve tried to be more diverse more recently. On initial diagnosis, some 70% in both arms had de novo metastatic disease. They weren’t patients who slowly crept up and had a little bit of metastatic disease, so these are probably worse [risk status] patients. In fact, 70% in both arms had high-volume disease on this trial. If you look at the performance status, 47% [in the experimental arm] had performance status 1 to 2. Performance status is also something rather subjective, so it could be that they were not the most [healthy] of patients, but they still did well.

What were the key efficacy outcomes of this trial?

These are the results in terms of rPFS by central review: at 24 months, with the darolutamide and ADT the median was not yet reached [vs 25.0 months with ADT]. It was 73% who had no radiologic progression compared with 52% of those [receiving] ADT. We reduced the risk of radiologic progression or death by 46%; the HR was 0.54 [95% CI, 0.41–0.71; P <.0001]. The benefit was consistent across all of the subgroups: the high volume and even the low volume as well. They all did well. All of the subgroups did well with the combination…[which was] not a big surprise to any of us.

If we look at the secondary efficacy end points, at the time of the primary analysis, the OS data are immature, [but they are] crossing the hazard line of 1 [HR, 0.81; 95% CI, 0.59–1.12]. The time to metastatic [castration-resistanct prostate cancer] favors darolutamide [HR, 0.40; 95% CI, 0.32–0.51]. The time to of [prostate-specific antigen (PSA)] progression, the time to initiation of subsequent systemic therapy for prostate cancer, and the time to pain progression all favor the darolutamide plus ADT arm instead of just ADT and placebo.

The time to metastatic castration-resistant prostate cancer and time to of pain progression were favoring darolutamide. PSA response [achieving] less than 0.2 ng/mL at any time during treatment was much higher in those who got darolutamide. We published papers after the ARASENS trial showing that having a PSA of less than 0.2 ng/mL is an excellent prognostic feature,⁴ and it was 63% vs 19%;^2,3 time to PSA progression also favored the darolutamide. So, in all of these subgroup analyses, including low volume and high volume, darolutamide was better.

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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. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2026. Accessed October 28, 2025. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

2. 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

3. 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

4. Saad F, Hussain MHA, Tombal B, et al. Deep and durable prostate-specific antigen response to darolutamide with androgen deprivation therapy and docetaxel, and association with clinical outcomes for patients with high- or low-volume metastatic hormone-sensitive prostate cancer: Analyses of the randomized phase 3 ARASENS study. Eur Urol. 2024;86(4):329-339. doi:10.1016/j.eururo.2024.03.036