Limited Drug Antagonism Between Darolutamide and Docetaxel Confirms Efficacy and Tolerability of ARASENS Triplet in mHSPC

The addition of darolutamide (Nubeqa) to docetaxel and androgen deprivation therapy (ADT) does not negatively affect the pharmacokinetics of either darolutamide or docetaxel, further indicating that this triplet regimen can be effectively and safely provided as a standard of care to patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to Bertrand F. Tombal, MD, PhD.¹

The triplet regimen gained FDA approval for patients with mHSPC on August 2022 based on previously reported data from the phase 3 ARASENS trial (NCT02799602).1 In this trial, darolutamide plus docetaxel and ADT produced a 32.5% reduction in the risk of death vs docetaxel, ADT, and placebo in patients with mHSPC. A similar incidence of treatment-emergent adverse effects (TEAEs) was observed between both groups.²

In an analysis of the dosing, safety, and pharmacokinetics of docetaxel, ADT, and darolutamide co-administration, the triplet produced comparable rates of TEAEs, and a similar percentage of patients requiring dose reduction, modification, or discontinuation vs the placebo regimen. Moreover, darolutamide and docetaxel did not display significant drug-drug interactions. These data were presented at the 2023 Genitourinary Cancers Symposium.¹

Update data from a secondary analysis of this trial were also presented at the meeting and demonstrated improved overall survival with the triplet regardless of disease volume or risk status.³

“We had never [previously] shown the pharmacokinetics of [this combination],” Tombal said in an interview with OncLive®. “Although [this analysis] confirms what we have seen [in ARASENS], it was [still] important to show [these results].”

In the interview, Tombal, who is a professor and chair of the Division of Urology at the Cliniques universitaires Saint-Luc in Brussels, Belgium, discussed the importance of investigating clinically relevant drug-drug interactions and TRAEs with the triplet regimen, explained how these data support previously reported efficacy data from the ARASENS trial, and presented lingering questions and caveats from this trial that should be addressed through continued research.

OncLive: You coauthored the latest analysis from the ARASENS trial on dosing, safety, and pharmacokinetics with docetaxel plus darolutamide and ADT. What was the purpose and significance of this subsequent analysis, and what was learned regarding the pharmacokinetic profile of the regimen?

Tombal:We have been trying to combine docetaxel with more than 20 drugs in the castrate-resistant setting [for many years], but none of these trials were positive. One of the reasons was that the drug we used [often] interfered with the pharmacokinetics of docetaxel, resulting in a decrease of either docetaxel or the drug [being] tested. We chose darolutamide because it has a very favorable drug-drug interaction profile and does not interfere with the metabolism of docetaxel. These [updated] data were important to confirm that hypothesis.

We showed that darolutamide does not affect the pharmacokinetics of docetaxel, and vice versa. That explains why we don’t see any added toxicity or inferior efficacy when we combine both drugs. [Although this analysis] doesn’t [provide any] new [efficacy] data, it was very important to [confirm our hypothesis].

What questions have been generated by the trial results? What are some of the limiting factors that prevent interpretation?

When we speak about ARASENS, everybody asks [which] patients need docetaxel, [but] this was not [the purpose of] ARASENS. If you believe your patient needs docetaxel [in addition to] ADT, we are showing with a high degree of [certainty] that you need to [intensify treatment with darolutamide]. That’s the ARASENS paradigm. Having said that, the major bias is that [physicians enrolled] patients in the trial [who] they believe needed ADT plus docetaxel. Keep in mind that we are speaking about a very specific [population], which cannot only be defined by volume and risk. We’re going to have to do more trials to answer all the [remaining] questions that [we] have.

What questions remain regarding the use of this regimen in prostate cancer, and how can future research address them?

The next important question [centers around the efficacy of] ADT plus darolutamide alone. [In other words], is the efficacy of darolutamide only linked to docetaxel? I would say [it is not just linked to docetaxel], but we must show it [in ongoing] studies. Future [areas of interest] will [focus on treatment] duration. Should all patients receive treatment [indefinitely], especially when they don’t have very high-volume disease and respond very well? Most importantly, we were [evaluating] a triplet [of] ADT, plus docetaxel, plus darolutamide. There will be many more triplets with radionuclides [or] PARP inhibitors [coming down the pike]. We still have a lot of work to do.

[Whether or not] testing [should be required] with a PARP inhibitor combination is [another] hot topic [in prostate cancer]. I’m not absolutely convinced that [this approach] can be given broadly, but everybody’s got a [different] opinion. That is certainly going to be the next [big] topic [of debate] for the next 3 years.

What else is important to focus future research on in prostate cancer?

At my research institution, the European Organization for Research and Treatment of Cancer, I believe [it is] important to look at [whether we] can we stop treatment, or at least [shorten the duration of] treatment in patients treated with modern ADT [who have a] major prostate-specific antigen response. That’s a way to [determine] the oncological benefit [of treatment], while [decreasing adverse effects], improving quality of life, and saving resource[s. As a] rich country, [that] is not necessarily a major issue, but there are many places where you could [improve] access [for] more patients if you show that you can get the same effect by reducing the duration of treatment.

Disclosures: Dr Tombal reports serving as a consultant or in an advisory role for Astellas Pharma, Bayer, Ferring, Janssen, Myovant Sciences, Pfizer, Sanofi, Steba Biotech, Takeda; he reports institutional research funding from Ferring; he has served on the Speakers’ Bureau for Amgen, Astellas Pharma, Janssen; he received honoraria from Amgen, Astellas Pharma, Bayer, Ferring, Janssen, Myovant Sciences, Pfizer, and Sanofi.

References

1. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. News. FDA. August 5, 2022. Accessed April 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. Rezazadeh A, Tombal BF, Hussain MHA, et al. Dosing, safety, and pharmacokinetics (PK) of combination therapy with darolutamide (DARO), androgen-deprivation therapy (ADT), and docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study. J Clin Oncol. 2023;41(suppl 6):148. doi:10.1200/JCO.2023.41.6_suppl.148
3. Hussain MHA, Tombal BF, Saad F, et al. Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study. J Clin Oncol. 2023;41(suppl 6):15. doi: 10.1200/JCO.2023.41.6_suppl.15