Patient-centered outcomes and preference between darolutamide and enzalutamide: insights from the ODENZA trial

In the treatment of metastatic castrate-resistant prostate cancer (mCRPC), traditional androgen deprivation therapy (ADT) has given way to newer androgen receptor pathway inhibitors (ARPIs) as the preferred first-line treatment option (1). Four second-generation anti-androgens are currently approved in advanced prostate cancer: abiraterone, apalutamide, enzalutamide and darolutamide. Evidence on the exact effects of hormonal therapies on cognition and fatigue is notoriously mixed, with meta-analyses suggesting subjective cognitive decline without substantial impact on objective cognitive performance, albeit with substantial heterogeneity across studies (2). Early retrospective data on ARPIs signalled association with neurocognitive adverse effects, including fatigue and cognitive decline, which remain key considerations for patients in driving both treatment selection and adherence (3,4). Of the ARPIs, darolutamide has been proposed to cause fewer neurocognitive symptoms due to low penetrance of the blood-brain barrier, with demonstrated brain-plasma concentrations of 2–3% (compared to enzalutamide’s 27%) in mice (5). Though translation from an animal model to humans is not perfect, the phase III ARAMIS trial found that darolutamide’s neurocognitive effects were similar to placebo, and this has been inferred to represent negligible central nervous system (CNS) penetrance in patients with prostate cancer (6). However, there has been little high-quality prospective data comparing effects of ARPIs head-to-head. The AQUARIUS trial compared abiraterone and enzalutamide in a real-world, non-randomized setting and found that patients on abiraterone reported less fatigue and cognitive impairment in certain measures compared to enzalutamide (7). Meanwhile, Khalaf et al. compared health-related quality of life measures for abiraterone versus enzalutamide in a phase II randomized study and found that patients aged 75 years or older reported better quality of life over time with abiraterone, while no difference was found in younger patients (8). As potential neurocognitive effects remain of great importance to patients, the ODENZA trial is a welcome addition in comparing such patient-centered outcomes across two ARPIs: darolutamide and enzalutamide, in a randomized, crossover phase II study (9). Here, we explore the implications of these findings, placing them within the broader context of hormonal therapy’s impact on cognition and quality of life.

ODENZA evaluated darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic mCRPC at 21 French hospitals, assessing patient preference as the primary endpoint. Patients received each drug for 12 weeks in a randomized, crossover sequence without a washout period between treatments. The second treatment period was initiated unless there was evidence of disease progression. Patient preference was measured after 24 weeks, at the end of the crossover phase, with reasons for preference recorded as a secondary outcome. Other secondary outcomes were cognitive performance (measured with a computerized neuropsychological battery), fatigue, and depression measured through standardized and validated tools at baseline, end of first treatment period (12 weeks) and end of second treatment period (24 weeks). After 24 weeks, patients entered an extension phase during which they received their preferred treatment until disease progression or unacceptable toxicity, however, this was not the primary focus of the trial and mainly provided additional data on safety and tolerability.

Ultimately, although more patients preferred darolutamide than enzalutamide, no statistical difference was found in patient preference across treatments. Among the 200 patients who completed both treatment periods, 97 (49%) preferred darolutamide, 80 (40%) preferred enzalutamide, and 23 (11%) expressed no preference, but there was no statistically significant difference in preference (P=0.92). This was counter to the authors’ original hypothesis that substantially more patients would prefer darolutamide. Regardless of preference or lack thereof, the most common factors participants attributed as influencing preferred treatment choice were quality of life, fatigue and ease of administration. Given the signal across secondary neurocognitive outcomes favoring darolutamide, one wonders whether there was inadequate power to detect separation in patient preference at a smaller difference than expected. The authors calculated their required sample size with an estimate that 38% of patients would prefer darolutamide and 22% for enzalutamide, but the results did not reflect this large difference. Regardless, based on available data, our cautious view in light of lack of statistical difference is that there was no convincing preference between these two agents demonstrated overall, although the stated reasons driving preference continue to highlight prioritization of patient-centered outcomes affecting quality of life (10).

In the secondary outcomes, darolutamide was favored over enzalutamide in verbal learning and reported fatigue. There is certainly plausibility to darolutamide’s superiority in neurocognitive adverse effects, with its aforementioned low penetrance of the blood-brain barrier and neurocognitive effects similar to placebo demonstrated in ARAMIS (5,6). The effect sizes in the ODENZA trial, however, did not reflect such a large discrepancy. The authors selected a battery of 6 brief cognitive tests across 3 main cognitive domains: attention, executive function, and memory. Darolutamide demonstrated a statistically significant advantage in cognitive testing across three measures of memory using a 12-item shopping list: (I) verbal learning with immediate recall, (II) verbal memory with delayed recall and (III) a composite score of the prior two tests. Immediate and delayed recall use the same encoded list (as is commonly done for measures of amnestic deficits) and the third measure selected is a composite of the other two, so the finding of significant differences across these three measures of memory may be more limited than reported. Furthermore, the clinical significance of differences is questionable. There is no validated minimal clinically important difference (MCID) for these scales, but the authors estimated effect size of ≥0.5 as clinically meaningful a priori. The reported effect sizes of 0.5 for the composite score and 0.5 for the immediate recall therefore only just met this threshold, while the delayed recall effect size of 0.3 did not, suggesting lack of clinical significance. In contrast to these effect sizes, the International Cognition and Cancer Task Force (ICCTF) notably recommends consideration of scores at least 1.5–2.0 standard deviation below the normative mean in the criteria to assess for cognitive impairment (11). Patients also reported less fatigue with darolutamide than with enzalutamide. The mean Brief-Fatigue Inventory (BFI) score was 2.7 with darolutamide and 3.3 with enzalutamide, from 2.5 at baseline. A recent study in cancer patients suggested a difference of 1.33-1.76 in the BFI is clinically meaningful (12). The true impact of a difference of around 0.6 in BFI score between darolutamide and enzalutamide displayed in ODENZA is therefore unclear.

ODENZA’s secondary outcomes therefore signal darolutamide’s superiority on select cognitive measures and fatigue, but with effect sizes at or below proposed thresholds for clinical merit that do not reflect the large difference in brain-plasma concentration compared to enzalutamide. This suggests that there are more complex factors driving these symptoms in people with mCRPC than simply the degree of CNS penetrance of the individual ARPI. Adding to this was the fact that there was no difference found among other cognitive domains examined in ODENZA, with two tests in attention and two tests in executive function and their respective composite scores all comparable between the two ARPIs. These are domains that have been frequently implicated in the effects of hormonal therapy (2). With a complex, multifaceted outcome such as cognition, increasing the number and variety of tests across different domains would have certainly improved sensitivity; however we understand that these are time and resource intensive. While the tests selected by the authors have been used in other studies involving prostate cancer treatments and cognition, substantial heterogeneity across the larger body of literature has been a substantial challenge in synthesizing evidence in meta-analysis (2). It is also notable that ODENZA found no difference in depression scores between groups, another frequent symptom of concern in ARPIs (3,4).

The modest findings when comparing these agents head-to-head may be surprising in the context of their individual phase III trials and other bodies of evidence. Darolutamide showed great promise in the original ARAMIS trial, where metastasis-free survival was increased while markers of fatigue and cognition were similar to placebo in non-mCRPC (6). Meanwhile, the PROSPER trial examined enzalutamide in non-mCRPC and demonstrated increased metastasis-free survival but with significant increase in fatigue, falls, cognitive impairment, and a small increase in seizure risk compared to placebo, which was attributed to the CNS penetrance (13). In 2021, Batra et al.’s systematic review of 15 ARPI studies excluded darolutamide but found potential cognitive detriments with enzalutamide while there were minimal cognitive changes with abiraterone, albeit with limited evidence (3). The aforementioned AQUARIUS study found that patients on abiraterone reported less fatigue and cognitive impairment in certain measures compared to enzalutamide, while Khalaf et al.’s 2019 study found better quality of life reported by older patients with abiraterone compared to enzalutamide (7,8). The stage was therefore set for darolutamide to display improved neurocognitive outcomes over enzalutamide, but ODENZA’s findings were ultimately modest and did not show patients’ strong preference of one agent over the other, even though the participants highlighted the importance of adverse effects such as fatigue in treatment choice.

This may be in part due to the trial’s design. ODENZA has several strengths, including a good sample size of 200 patients, enhancing its statistical reliability, and clinically relevant endpoints such as patient preference, cognitive outcomes, and fatigue—factors that are highly relevant in real-world decision-making for mCRPC. Additionally, the trial’s median age of 72 aligns with the typical geriatric oncology population, where treatment preferences and side effect profiles are particularly impactful with prevalence of multiple comorbidities, frailty, and frequent polypharmacy that can independently lead to cognitive complaints and fatigue. However, it has notable limitations: the lack of a washout period raises concerns about potential carryover effects (even though robust statistical methods were evaluated for period effect), and while subjective preferences and cognitive outcomes were evaluated, the study’s short duration of 12 weeks per drug precludes insights into longer-term cognitive changes. These are more commonly assessed over 6–12 months or during prolonged therapy spanning several years, given that the clinical timeline of cognitive decline is typically longer and hormone treatment with ARPI is often for 1 to 3 years. The prior phase III trials that showed potential for darolutamide’s superiority over enzalutamide in quality-of-life measures had substantially longer mean follow-up periods (ARAMIS 29 months, PROSPER 33 months), though cognition was neither the focus nor objectively measured. Although the exclusion of washout period was unavoidable in this study due to risk of cancer progression, one wonders whether a design which avoids crossover and includes a longer follow-up period would have shown more convincing separation in outcomes between the two drugs. However, this would not have allowed for patient preference to be assessed, and the authors’ choice of design to reflect a primary outcome rooted in patient-centred care is particularly laudable.

Overall, although prior studies, including preclinical and non-randomized clinical data, suggested that darolutamide may be superior in neurocognitive outcomes compared to enzalutamide, ODENZA showed that within this head-to-head comparison, people with mCRPC did not generally prefer one agent over another, even though they cited fatigue and quality-of-life as driving their preferences. Select secondary outcomes specific to fatigue and verbal episodic memory showed statistical difference favouring darolutamide, but the true clinical impact of those findings remains uncertain with effect sizes just at or below the threshold for clinical relevance. Therefore, although this study may not have substantially shifted the body of evidence regarding choice of ARPIs, it is an excellent addition to the limited number of prospective ARPI trials with a focus on patient-centered outcomes. It reinforces the fact that neurocognitive effects and quality-of-life are crucial for patient decision-making; patient preferences drive medication adherence and therefore treatment efficacy, so we must involve them in decision-making despite the uncertainty of evidence. Shared decision making (SDM) which actively involves the patient in co-creation of management plans is increasingly recognized as an approach which increases patient satisfaction in cancer management (14-16). Clinical tools are being actively developed to facilitate co-created plans which address the priorities of each patient in the context of their individual problems and personal values (17). Amongst those, patient decision aids (PDAs) have shown promise and are being developed for prostate cancer patients (18). However, none specific to ARPIs currently exist and many gaps remain in our knowledge of what drives patient decisions in advanced prostate cancer (19). Nonetheless, ODENZA’s insights on patient values add further support to the common clinical practice of switching ARPIs in those who experience toxicities such as fatigue and cognitive concerns and encourage the SDM approach. Further ARPI trials including those with longer follow-up periods will provide greater clarity on how patient experience differs across these different agents and may aid in creation of PDAs amongst other clinical tools furthering SDM. Meanwhile, whether darolutamide’s favourable pharmacological profile truly results in better quality-of-life when compared to other ARPIs remains to be definitively demonstrated.

Acknowledgments

None.

Footnote

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