Impact of androgen receptor pathway inhibitors on cognitive function in elderly patients treated for metastatic prostate cancer

Antoine Boué 1

Giulia Baciarello 2

Emmanuel Meyer 3

François Christy 4

Marie Lange 13✉ Phone*+33 2 31 45 86 09 Emailm.lange@baclesse.unicancer.fr

INSERM Anticipe 1

1 University of Caen Normandie 1086, 14000 Inserm, Anticipe, Caen France

2 cancer medicine department Gustave Roussy 94805 Villejuif France

3 François Baclesse center, radiation oncology department 14000 Caen France

4 François Baclesse center, clinical research department 14000 Caen France

5 Services unit PLATON, Cancer and cognition platform University of Caen Normandie 14000 Caen France

6 François Baclesse center, medical oncology department 14000 Caen France

7 medical oncology department Foch hospital 92150 Suresnes France

8 supportive care department, psycho-oncology unit Montpellier cancer institute (ICM) 34090 Montpellier France

9 medical oncology department Montpellier cancer institute (ICM) 34090 Montpellier France

10 medical oncology department Amiens-Picardie university hospital center 80054 Amiens France

11 Henri Becquerel center, medical oncology department 76038 Rouen France

12 medical oncology department Caen university hospital center 14000 Caen France

13 François Baclesse Center *3 avenue du général Harris 14000 Caen France

Antoine Boué^a, Giulia Baciarello^b, Emmanuel Meyer^c, François Christy^d,e, Nedjla Allouache^f, Raffaele Ratta^g, Philippe Beuzeboc^g, Pierre-Emmanuel Brachet^f, Estelle Guerdoux^h, Amélie Darlixⁱ, Mathieu Boone^j, Sophie Gouerant^k, Alexandra Leconte^d, Justine Lequesne^d,e,

Bénédicte Clarisse^d, Karim Fizazi^b, Marie Lange^a,d,e*, Florence Joly^a,d,e,f,l

^a University of Caen Normandie, Inserm 1086 Anticipe, 14000 Caen, France

^b Gustave Roussy, cancer medicine department, 94805 Villejuif, France

^c François Baclesse center, radiation oncology department, 14000 Caen, France

^d François Baclesse center, clinical research department, 14000 Caen, France

^e University of Caen Normandie, Services unit PLATON, Cancer and cognition platform, 14000 Caen, France

^f François Baclesse center, medical oncology department, 14000 Caen, France

^g Foch hospital, medical oncology department, 92150 Suresnes, France

^h Montpellier cancer institute (ICM), supportive care department, psycho-oncology unit, 34090 Montpellier, France

ⁱ Montpellier cancer institute (ICM), medical oncology department, 34090 Montpellier, France

^j Amiens-Picardie university hospital center, medical oncology department, 80054 Amiens, France

^k Henri Becquerel center, medical oncology department, 76038 Rouen, France

^l Caen university hospital center, medical oncology department, 14000 Caen, France

*Marie Lange

*INSERM 1086 Anticipe

*François Baclesse Center,

*3 avenue du général Harris, 14000 Caen, France

*+33 2 31 45 86 09

*m.lange@baclesse.unicancer.fr

*Corresponding author:

Word count of text: 2532

Word count of abstract: 177

version 20241216

Abstract

Androgen receptor pathway inhibitors (ARPI) are commonly used in addition to androgen deprivation therapy (ADT) for metastatic prostate cancer (mPC). However, there is limited data on their cognitive impact in elderly patients. This prospective multicenter trial recruited castration-resistant mPC patients aged ≥ 70 receiving ADT + ARPI, patients receiving ADT alone, and healthy controls (HC). Cognition was assessed with a self-report questionnaire (subjective cognition) and cognitive tests addressing six domains: processing speed/attention, working memory, verbal memory, visual memory, visuospatial abilities, and executive functions (objective cognition). At baseline (before starting ARPI for ADT + ARPI patients), objective cognitive impairment concerned 36 (51%), 5 (26%) and 3 (10%) ADT + ARPI patients, ADT patients and HC, respectively. After 3 and 6 months of follow-up, adjusted scores showed poorer subjective cognition in ADT + ARPI patients than in ADT patients (p ≤ 0.033). ADT + ARPI patients also had lower objective performance in processing speed/attention domain at all visits (p ≤ 0.010). Although limited by small sample sizes, our study shows for the first time that ARPI + ADT can increase the risk of impacting objective and subjective cognition in elderly mPC patients, compared to ADT alone.

Keywords

Androgen receptor pathway inhibitors

Cancer-related cognitive impairment

Elderly

Metastatic prostate cancer

Introduction

Enzalutamide and abiraterone acetate are the first agents of the second generation of androgen receptor pathway inhibitors (ARPI) for metastatic prostate cancer (mPC). Demonstrating a large benefit on survival compared to standard androgen deprivation therapy (ADT) alone, they have become the standard of care for castration-resistant mPC (mCRPC)[1] and hormone-sensitive mPC (mHSPC)[2]. While they are generally well tolerated, ADT and ARPI can have side-effects on cognition[3]. These are of particular concern in elderly patients, who are at increased risk of cognitive impairment[4], with potential repercussions on autonomy, quality of life and cancer-related mortality[5, 6].

Preliminary results suggested an association between ARPI and cognitive impairment[7], particularly with enzalutamide[8]. Most studies to date focused on the frequency of adverse events reported in medical charts, or were based on cognitive screening tests (e.g. Montréal Cognitive Assessment, MoCA[9]). These measures do not make it possible to identify which domains of objective cognition are most impacted. One study using specific cognitive measures showed lower verbal memory in patients treated with enzalutamide compared with darolutamide[10]. Another study using questionnaires showed poorer subjective cognition in patients treated with enzalutamide compared with abiraterone acetate[11, 12]. However, neither of these studies compared patients receiving ARPI with patients receiving ADT alone[10–12]. Since ARPI are systematically combined with ADT to date, the specific effect of these new agents remains elusive.

The objectives of this trial were (i) to estimate the frequency of overall objective and subjective cognitive impairment before ARPI initiation and decline during treatment in elderly mPC patients, (ii) to describe differences in objective domains and subjective cognition between patients receiving ADT + ARPI and those receiving ADT alone, and (iii) to identify some baseline factors associated with cognitive changes.

Results

Between November 2016 and October 2021, 106 ADT + ARPI patients, 24 ADT patients and 33 healthy controls (HC) were included in a prospective, multicenter, comparative trial. Among the ADT + ARPI, ADT and HC groups, 32 (30%), 5 (21%) and 3 (9%) participants respectively were not considered for analyses, mainly due to withdrawal of consent before the 3-month visit (Fig. 1). The final sample included 74 ADT + ARPI patients, 19 ADT patients and 30 HC patients. Non-analyzed participants were older and had poorer geriatric outcomes. The most frequent reasons for subsequent dropouts were: discontinuation of treatment (n = 21), concomitant disease or disability impeding the administration of cognitive tests (n = 7) and withdrawal of consent (n = 4).

Fig. 1

Flow diagram of patients receiving ADT + ARPI, ADT and for HC

Baseline characteristics

The ADT + ARPI, ADT and HC groups had a mean age of 78, 74 and 75 years, respectively (p = 0.002, Table 1). At baseline (i.e. before ARPI initiation), patients had received previous androgen deprivation for a median duration of 13 months in the ADT + ARPI group and 21 months in the ADT group, with no significant difference (ns). In addition, 14 (22%) ADT + ARPI patients and 1 (5%) ADT patient had received analgesic treatment (ns). Compared with the ADT group, ADT + ARPI patients had poorer geriatric outcomes according to the G8 screening tool[13], Instrumental activities of daily life (IADL)[14], and Timed up and go[15] (p ≤ 0.030).

Table 1

Participants’ baseline characteristics
	ADT + ARPI n = 74	ADT n = 19	HC n = 30	p
Demographic data
Age, years: mean (SD)	78.2 (6.09)	74.4 (3.95)	74.7 (4.41)	0.002
Married/cohabiting: n (%)	59 (80%)	15 (79%)	27 (90%)	0.423
Education, years of schooling: mean (SD)	12.6 (3.55)	12.0 (2.65)	13.7 (3.08)	0.179
Clinical data
ECOG performance status	_e			0.002
0: n (%)	31 (45%)	17 (89%)
1: n (%)	32 (46%)	2 (11%)
2: n (%)	6 (9%)	0 (0%)
Body mass index, kg/m²: mean (SD)	27.8 (3.55)ⁱ	28.2 (5.16)^b		0.762
Charlson index: mean (SD)	1.19 (1.29)	0.95 (1.18)		0.440
Psychotropic drugs: n (%)	9 (12%)	2 (11%)		1.000
Analgesic drugs : n (%)	16 (22%)	1 (5%)		0.180
ADT duration, months: median (IQR)	13.0 (2.8–28.2)^b	21.1 (9.4–48.6)		0.094
Previous treatment
Chemotherapy: n (%)	3 (4%)	0 (0%)		1.000
Radiotherapy: n (%)	55 (74%)	18 (95%)		0.064
Time since diagnosis, years: mean (SD)	14.6 (6.87)	15.4 (5.83)		0.573
Testosterone, abnormal: n (%)	64 (91%)^d	16 (89%)^a		0.664
TSH, abnormal: n (%)	7 (10%)^d	0 (0%)^b		0.337
PSA, abnormal: n (%)	49 (80%)^h	4 (24%)^b		< 0.001
Gleason score	_f			0.746
4–6: n (%)	12 (18%)	4 (21%)
≥7: n (%)	55 (82%)	15 (79%)
d’Amico risk classification	_g			0.221
low: n (%)	0 (0%)	1 (5%)
intermediate: n (%)	14 (22%)	5 (26%)
high: n (%)	49 (78%)	13 (69%)
Initially metastatic: n (%)	17 (23%)	4 (21%)		1.000
Geriatric data
G8 screening tool: mean (SD)	14.6 (3.06)	16.1 (1.77)		0.007
IADL: mean (SD)	5.59 (1.00)	5.87 (0.23)		0.030
MNA: mean (SD)	26.5 (2.10)^j	27.3 (2.13)^c		0.205
Timed up and go: mean (SD)	3.73 (1.01)	4.00 (0.00)		0.024
Premorbid intellectual functioning and cognitive screening
fNART: mean (SD)	26.9 (6.66)^c	26.1 (6.97)^a	29.2 (5.72)	0.193
MoCA: mean (SD)	24.0 (3.53)	25.9 (3.45)	27.2 (1.76)	< 0.001
Other PROs
HADS – total, symptomatic: n (%)	24 (34%)^c	3 (17%)^a	4 (13%)	0.075
depression: mean (SD)	4.19 (3.33)^c	3.57 (2.73)^a	3.47 (2.67)
anxiety: mean (SD)	5.18 (3.10)^c	5.00 (3.16)^a	5.03 (3.29)
ISI, symptomatic: n (%)	13 (18%)^c	1 (6%)^a	1 (3%)	0.075
FACIT-F, symptomatic: n (%)	30 (42%)^c	4 (22%)^a	1 (3%)	< 0.001
Visual analogue scale: mean (SD)	2.34 (2.41)^g	2.65 (3.10)^a	1.58 (1.76)	0.244
ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. ECOG: Eastern Cooperative Oncology Group. FACIT-F: Functional Assessment of Chronic Illness Therapy – Fatigue. fNART: French National Adult Reading Test. HADS: Hospital Anxiety and Depression Scale. HC: healthy controls. IADL: Instrumental Activities of Daily Life. IQR: interquartile range. ISI: Insomnia Severity Index. MoCA: Montréal Cognitive Assessment. MNA: Mini-Nutritional Assessment. PROs: Patient reported outcomes. PSA: prostatic specific antigen. SD: standard deviation. TSH: thyroid-stimulating hormone.
Missing data: ^an=1 ^bn=2 ^cn=3 ^dn=4 ^en=5 ^fn=7 ^gn=11 ^hn=13 ⁱn=14 ^jn=19

There was a difference between groups for cognitive status (MoCA[9], p < 0.001), with the lowest mean scores observed in the ADT + ARPI group. Fatigue (Functional Assessment of Chronic Illness Therapy - Fatigue, FACIT-F[16]) was reported in 30 (42%) ADT + ARPI, 4 (22%) ADT and 1 (3%) HC (p < 0.001). There was no significant difference in the levels of depression, anxiety and pain between groups. Among the ADT + ARPI group, patients treated with enzalutamide had more comorbidities than patients treated with abiraterone acetate (mean Charlson index: 1.41 vs. 1.19, p = 0.040, Supplementary information 1).

Cognitive outcomes in all patients (ADT+/-ARPI) compared with HC

At baseline, 41 (46%) of all patients had overall objective cognitive impairment vs. 3 (10%) HC (p < 0.001, Table 2), and 21 (24%) and 16 (18%) of all patients had subjective cognitive impairment according to the Perceived cognitive impairment (PCI) and abilities (PCA) subscale of the Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)[17] questionnaire, vs. 2 (7%) of HC on both subscales (ns). During follow-up, there was no significant difference in the frequency of overall objective or subjective decline (Table 3).

Table 2

Cognitive impairment at baseline according to treatment group (unadjusted)
	All patients (ADT+/-ARPI)			ADT + ARPI			ADT			HC		p³
	z	impairment		z	impairment		z	impairment		impairment		All patients vs. HC	ADT + ARPI vs. ADT
Baseline		n = 93			n = 74			n = 19		n = 30
Overall objective impairment¹		46%	(41)		51%	(36)		26%	(5)	10%	(3)	< 0.001	0.072
Processing speed/attention	-0.977	24%	(22)	-1.171	28%	(21)	-0.221	5%	(1)	3%	(1)
Working memory	-0.530	8%	(7)	-0.487	4%	(3)	-0.700	21%	(4)	0%	(0)
Verbal memory	-0.880	34%	(31)	-1.055	42%	(30)	-0.216	5%	(1)	10%	(3)
Visual memory	0.015	9%	(8)	-0.053	11%	(8)	0.279	0%	(0)	7%	(2)
Visuospatial abilities	-0.408	29%	(27)	-0.412	30%	(22)	-0.396	26%	(5)	7%	(2)
Executive functions	-0.901	59%	(48)	-1.004	60%	(37)	-0.518	58%	(11)	20%	(6)
Subjective impairment²
PCI		24%	(21)		24%	(17)		22%	(4)	7%	(2)	0.059	1.000
PCA		18%	(16)		20%	(14)		11%	(2)	7%	(2)	0.236	0.509
ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. PCI: Perceived cognitive abilities. PCI: Perceived cognitive impairment.
¹ Proportion of participants impaired in at least two objective domains according to ICCTF guidelines[32].
² Proportion of participants with a FACT-Cog – PCI and PCA score of ≤ 10th percentile of norms[39].
³ Comparison of percentage of participants with cognitive impairment. χ² or Fisher exact test. significant difference: p < 0.05.

Table 3

Cognitive decline during follow-up according to treatment group (unadjusted)
	All patients (ADT+/-ARPI)			ADT + ARPI			ADT			HC		p³
	RCI	decline		RCI	decline		RCI	decline		decline		All patients vs. HC	ADT + ARPI vs. ADT
3-month		n = 93			n = 74			n = 19		n = 30
Overall objective decline¹		3%	(3)		3%	(2)		5%	(1)	0%	(0)	1.000	0.500
Processing speed/attention	-0.209	5%	(5)	-0.281	7%	(5)	0.063	0%	(0)	3%	(1)
Working memory	-0.304	2%	(2)	-0.411	3%	(2)	0.105	0%	(0)	0%	(0)
Verbal memory	0.025	5%	(4)	0.117	3%	(2)	-0.323	11%	(2)	3%	(1)
Visual memory	-0.620	19%	(17)	-0.670	21%	(15)	-0.430	11%	(2)	0%	(0)
Visuospatial abilities	0.077	1%	(1)	0.044	1%	(1)	0.196	0%	(0)	0%	(0)
Executive functions	0.132	0%	(0)	0.209	0%	(0)	-0.148	0%	(0)	0%	(0)
Subjective decline²
PCI		22%	(18)		25%	(16)		11%	(2)	17%	(5)	0.792	0.335
PCA		27%	(23)		26%	(17)		33%	(6)	30%	(9)	0.815	0.558
6-month		n = 71			n = 54			n = 17		n = 28
Overall objective decline¹		4%	(3)		6%	(3)		0%	(0)	0%	(0)	0.556	1.000
Processing speed/attention	-0.055	3%	(2)	-0.037	4%	(2)	-0.117	0%	(0)	0%	(0)
Working memory	-0.174	3%	(2)	-0.236	4%	(2)	0.033	0%	(0)	0%	(0)
Verbal memory	0.046	2%	(1)	0.048	2%	(1)	0.040	0%	(0)	4%	(1)
Visual memory	-0.423	3%	(2)	-0.440	4%	(2)	-0.370	0%	(0)	4%	(1)
Visuospatial abilities	-0.274	8%	(5)	-0.377	10%	(5)	0.045	0%	(0)	0%	(0)
Executive functions	0.152	0%	(0)	0.207	0%	(0)	-0.017	0%	(0)	0%	(0)
Subjective decline²
PCI		27%	(18)		34%	(17)		6%	(1)	32%	(9)	0.628	0.050
PCA		41%	(27)		46%	(23)		25%	(4)	25%	(7)	0.165	0.158
12-month		n = 55			n = 42			n = 13		n = 29
Overall objective decline¹		4%	(2)		2%	(1)		8%	(1)	0%	(0)	0.542	0.420
Processing speed/attention	-0.202	5%	(3)	-0.256	5%	(2)	-0.027	8%	(1)	0%	(0)
Working memory	-0.184	0%	(0)	-0.297	0%	(0)	0.182	0%	(0)	0%	(0)
Verbal memory	-0.218	10%	(5)	-0.227	8%	(3)	-0.191	15%	(2)	0%	(0)
Visual memory	-0.346	7%	(4)	-0.385	7%	(3)	-0.220	8%	(1)	0%	(0)
Visuospatial abilities	-0.112	2%	(1)	-0.157	2%	(1)	0.027	0%	(0)	3%	(1)
Executive functions	-0.110	2%	(1)	0.016	2%	(1)	-0.496	0%	(0)	0%	(0)
Subjective decline²
PCI		35%	(18)		41%	(16)		17%	(2)	24%	(7)	0.329	0.174
PCA		39%	(20)		41%	(16)		33%	(4)	31%	(9)	0.629	0.743
ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. RCI: reliable change index. PCI: Perceived cognitive abilities. PCI: Perceived cognitive impairment.
¹ Proportion of participants declining in at least two objective domains according to RCI
² Proportion of participants with a FACT-Cog – PCI and PCA score decreasing ≥ 10% from baseline
³ Comparison of percentage of participants with cognitive decline. χ² or Fisher exact test. Significant difference: p < 0.05

When considering adjusted scores, patients performed significantly worse than the HC group at 3 months in all assessed objective domains except visual memory (Fig. 2). Between-group differences remained significant throughout follow-up for processing speed/attention, working memory, verbal memory and executive functions. Patients also had poorer subjective cognition according to PCI at each visit.

Fig. 2

Adjusted cognitive scores during 12-month follow-up in all patients (ADT+/-ARPI) and HC

ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. Multivariable linear models, adjusted for baseline cognition, age, education and fatigue. Low scores reflect poor cognition.

* p < 0.050, ** p < 0.010, *** p < 0.001. ¹ Adjusted composite Z-scores ² Adjusted FACT-Cog – PCI and PCA raw scores.

Cognitive outcomes in ADT + ARPI group compared with ADT

At baseline, 36 (51%) ADT + ARPI patients vs. 5 (26%) ADT patients had overall objective cognitive impairment (ns, Table 2). Subjective cognitive impairment according to PCI and PCA was observed in respectively 17 (24%) and 14 (20%) ADT + ARPI patients, vs. 5 (22%) and 2 (11%) ADT patients (ns). During follow-up, the highest rates of overall objective cognitive decline were observed at 6 months after ARPI initiation for ADT + ARPI patients (6%), with no difference with ADT patients (Table 3). For subjective cognition, 17 (34%) ADT + ARPI patients declined at 6 months in PCI, vs. 1 (6%) ADT patient (p = 0.050).

Considering adjusted scores (including previous ADT duration), ADT + ARPI patients had lower performance compared to the ADT group at 3 months in processing speed/attention (p = 0.007, Fig. 3). These significant differences persisted at 6 (p = 0.006) and 12 months (p = 0.010). There was a decrease in adjusted scores in the majority of objective domains between baseline and the 3-month visit. Even when there was a decrease after the introduction of ARPI, scores then increased between 6 and 12 months in 5 out of 6 objective domains. For subjective cognition, a decrease in scores was also observed up to 6 months, before stabilizing up to 12 months. In addition, ADT + ARPI patients reported poorer subjective cognition compared to ADT, with lower PCA at 3 (p = 0.033) and 6 months (p = 0.015), and a trend for PCI at 3 months (p = 0.065).

Fig. 3

Adjusted cognitive scores during 12-month follow-up according to treatment group

Among the ADT + ARPI group, 19 patients (41%) treated with enzalutamide and 17 (68%) patients treated with abiraterone acetate had overall objective cognitive impairment at baseline (Supplementary information 2). During follow-up, the highest rates of overall objective cognitive decline were observed at 6 months in both subgroups (6%). Almost a quarter of enzalutamide and abiraterone patients had subjective cognitive impairment before treatment initiation. Subjective cognitive decline also reached higher rates at 6 months in abiraterone acetate patients (PCA: 67%), and at 12 months in enzalutamide patients (PCA: 46%).

Baseline factors associated with cognitive changes in ADT + ARPI patients

A lower estimate of premorbid intellectual functioning (French National Adult Reading Test, fNART[18]) was associated with decreasing scores in working memory (3 months and 6 months, p = 0.016 and p = 0.022, respectively) and processing speed/attention (6 months, p = 0.021). Other important factors included fatigue (FACIT-F), which was associated with decreasing scores in visuospatial abilities (6 months, p = 0.048), visual memory (12 months, p = 0.021) and subjective cognition (e.g. PCI at 3 months, p = 0.036, Supplementary information 3).

Discussion

This trial aimed to evaluate the impact of ADT + ARPI on both objective and subjective cognition in elderly mPC patients, marking the first comparison with patients receiving ADT alone. Our results showed poorer cognition in patients receiving hormonal treatments, particularly when treated with ADT + ARPI.

At baseline, 46% of mPC patients treated with hormone therapy had overall objective cognitive impairment, (vs. 10% of HC). This mPC group comprised both ARPI candidates and ADT patients already treated with ADT for a median duration exceeding one year. ADT is suspected of negatively impacting cognition from the third month of treatment[19]. Previous studies showed that up to 69% of patients treated with ADT experienced a decline in at least one objective domain following the start of treatment[20], which makes our baseline impairment rate potentially reflective of the cognitive impact of androgen suppression. Among mPC patients, objective cognitive impairment was reported at baseline in 51% of those assigned to ADT + ARPI, a higher rate than in the ADT group (21%). However, these patients had more advanced disease than ADT patients with a high consumption of analgesic drugs, which is also likely to contribute to cognitive impairment[21].

During follow-up, there was no difference in rates of overall objective cognitive decline between patients and HC. In ADT + ARPI patients, these rates did not exceed 6%. This finding is in line with that of a previous ADT + ARPI cohort which experienced a 5% decline in objective cognition at two months of treatment[22]. However, adjusted domain-specific scores showed lower performance with ADT + ARPI compared to ADT in processing speed/attention. To our knowledge, this is the first comparison of the objective cognitive effects of ADT + ARPI with those of ADT alone.

Regarding subjective cognition, mPC patients reported greater impairment than HC throughout follow-up (adjusted PCI scores). Similarly, a meta-analysis showed a decline in subjective cognition during treatment with ADT alone, or in addition with ARPI[23]. However, it did not allow the effects of the two generations of hormone therapy to be distinguished. In the present study, ADT + ARPI patients reported poorer subjective cognition than those receiving ADT alone.

Among ADT + ARPI patients, objective and subjective impairment were frequent at baseline in the enzalutamide and abiraterone acetate subgroups. The introduction of ARPI was followed by subjective cognitive decline, regardless of the treatment. One study reported a higher risk of subjective cognitive impairment in patients treated with enzalutamide than in those treated with abiraterone acetate[11, 12]. However, previous studies that used specific measures of objective cognition did not show any difference between the two treatments[22, 24].

The COG-PRO trial focused on the cognitive impact of ARPI in elderly patients. This population is particularly sensitive to cognitive impairment associated with cancer and its treatments[4]. In our sample, ADT + ARPI patients were older and had poorer geriatric outcomes than ADT patients. Age itself is correlated with hormonal, cerebral, and subsequent cognitive changes. In addition to impacting the autonomy of elderly patients, decline in cognition can affect the course of care by impeding the ability to make decisions in relation to increasingly complex treatment pathways, and it can compromise compliance with oral therapies[25]. In addition, performance in processing speed/attention could impact autonomy in older adults, including money management and time planning[26].

The compensatory abilities developed by patients to cope with changes in cognition are supported by their cognitive reserve[27]. This phenomenon of cognition resisting neuropathological damage is partially subsumed by premorbid intellectual functioning related to development, education, and lifestyle. In our ADT + ARPI, patients the fNART score was associated with processing speed/attention and working memory. Moreover, subjective cognitive changes (PCI) in the ADT + ARPI group were associated with fatigue, i.e. a symptom frequent in elderly cancer patients[28]. Fatigue could affect 43% of patients treated with ADT, and there is growing evidence of its association with subjective cognitive impairment during treatment[29]. The risk of fatigue is also known to increase during treatment with ARPI[7], especially with enzalutamide[11, 12].

The small size of the ADT group and subgroups of patients treated with enzalutamide and abiraterone acetate is one limitation of this study. In addition, ARPI had no indication for mHSPC at the start of the inclusion, and selected mCRPC patients could exhibit greater frailty. This frailty and the length of the cognitive assessment may explain the frequency of requests to withdraw consent between baseline and the 3-month visit.

The introduction of ARPI in the earlier stages of prostate cancer, coupled with the increasing life expectancy of patients, is resulting in a longer duration of administration. The long-term comparison of different ARPI in a homogeneous population (i.e. in mHSPC) would be useful to characterize their respective impacts. In addition, measures of subjective cognition are increasingly implemented in cognitive cancer research, as it can impact quality of life[30]. A better understanding of the predictors of these outcomes, both objective and subjective, could enhance the detection of patients at risk of cognitive decline. The challenge is to inform patients before initiating treatments, to anticipate the onset of cognitive impairment and, if necessary, to propose strategies to manage cognitive changes and their consequences.

In conclusion, this study supports previous results demonstrating the impact of hormone therapy on cognition, and shows how it can be exacerbated by ARPI when added to ADT. To assess treatment-induced cognitive changes, clinicians should use specific measures of objective and subjective cognition.

Methods

Participants and procedure

COG-PRO (NCT02907372) was a prospective, multicenter, comparative trial, approved by an independent ethics committee. The protocol has been previously described[31]. ADT + ARPI and ADT groups were included in six French hospitals following the treatment decision of the participating physicians. The ADT + ARPI patient group had mCRPC and had to be candidates for treatment by enzalutamide or abiraterone acetate. The ADT patient group had been treated for mHSPC for at least 3 months.

The group of HC was recruited though local advertisements. ADT + ARPI, ADT and HC participants were aged ≥ 70 without neurological sequelae of brain impairment or neurodegenerative disease (Table 4). Clinical data were collected at baseline, prior to the initiation of treatment for ADT + ARPI patients. Cognitive data were collected at baseline and after 3, 6, and 12 months.

Table 4

Selection criteria
ADT + ARPI	ADT	HC
mCRPC Already treated with ADT Candidate for treatment with enzalutamide or abiraterone acetate	mHSPC Already started ADT for at least 3 months	No history of cancer
No chemotherapy except one line per docetaxel for hormone-sensitive disease and completed for at least 18 months prior to inclusion Asymptomatic or pauci-symptomatic (visual analogue scale ≤ 3) ECOG performance status ≤ 2 No known brain metastasis		No history of cancer
70 years old or more No neurological sequalae of brain impairment including traumatic brain injury, stroke, neuro-degenerative disease No personality disorders or known progressive psychiatric disorder No drug use including heavy drinking No inability or refusal to comply with requirements of protocol At least level 3 (end of primary school) on Barbizet scale Signed informed consent
ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. ECOG: Eastern Cooperative Oncology Group. HC: healthy controls. mCRPC: metastatic castration-resistant prostate cancer. mHSPC: metastatic hormone-sensitive prostate cancer.

Measures

Objective cognition was assessed with nine cognitive tests, selected according to the recommendations of the International Cognition and Cancer Task Force (ICCTF)[32] and previous studies on the cognitive impact of ADT[19]. Measures were grouped into six objective domains (Table 5) using an adaptation of an international classification of cognitive tests[33]: processing speed/attention, working memory, verbal memory, visual memory, visuospatial abilities, and executive functions. Subjective cognition was assessed with the PCI and PCA subscales of the FACT-Cog questionnaire[17]. In addition, cognitive status and premorbid intellectual functioning at baseline were assessed with MoCA[9] and the fNART[18], respectively.

Table 5

A: Cognitive measures and corresponding tests and questionnaires according to adapted classification of Lezak and colleagues[1]
Cognitive domain¹	Test or questionnaire (battery)	Measure
Processing speed/attention	Digit symbol-coding (WAIS-III)[42]	correct reproductions
	TMT (GREFEX)[43]	time A
Working memory	Digit span (WAIS-III)[42]	score forward
		score backward
Verbal memory	Grober-Buschke test (GREMEM)[44]	sum of three free recalls
	Grober-Buschke test (GREMEM)[44]	sum of three total recalls
		free delayed recall
		total delayed recall
Visual memory	Doors test[45]	test A
		test B
Visuospatial abilities	Rey-Osterrieth complex figure[46]	ECPA copy score[47]
Visuospatial abilities	Number location (VOSP)[48]	total score
Executive functions	Stroop Victoria[49]	time interference/colors
		total errors interference
	Verbal fluencies (GREFEX)[43]	letter fluency
		category fluency
	TMT (GREFEX)[43]	time B/A
		errors B
Subjective cognition	FACT-Cog[17]	PCI
		PCA
ECPA: Editions of the Center for Applied Psychology (France). FACT-Cog: Functional Assessment of Cancer Therapy - Cognitive Function. PCA: Perceived cognitive abilities. GREFEX: Task Force on Executive Function Assessment (France). GREMEM: Task Force on Memory Assessment (France). PCI: Perceived cognitive impairment. TMT: Trail-Making Test. VOSP: Visual Object and Space Perception battery. WAIS-III: Wechsler Adult Intelligent Scale, third edition.
¹ adaptations by consensus between two neuropsychologists (AB and ML) based on previous studies on the cognitive impact of androgen deprivation therapy[19]: separation of working memory from processing speed/attention, addition of a new domain referring to visuospatial abilities.

Table 5

B: Geriatric assessment and other PROs
Group	Dimension	Measure	Threshold value¹
Geriatric assessment	Geriatric frailty	G8 screening tool[13]	-
	Instrumental activities of daily life	IADL[14]	-
	Nutrition status	MNA[35]	-
	Mobility	Timed up and go[15]
Other PROs	Anxiety - Depression	HADS – total score[36]	≥ 13 [50]
	Insomnia	ISI[37]	≥ 15 [51]
	Fatigue	FACIT-F[16]	≤ 36 [51]
	Pain	Visual analogue scale[52]	-
FACIT-F: Functional Assessment of Chronic Illness Therapy - Fatigue. HADS: Hospital Anxiety and Depression Scale. IADL: Instrumental Activities of Daily Life. ISI: Insomnia Severity Index. MNA: Mini-Nutritional Assessment. PROs: Patient reported outcomes.
¹ if applicable, threshold value for qualifying a symptomatic outcome.
ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls.
ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. Multivariable linear models, adjusted for baseline cognition, age, education, fatigue and previous ADT duration. Low scores reflect poor cognition. * p < 0.050, p < 0.010, * p < 0.001. ¹ Adjusted composite Z-scores ² Adjusted FACT-Cog – PCI and PCA raw scores.

Geriatric data included screening for frailty (G8[13]), comorbidities (Charlson index[34]), instrumental activities of daily life (IADL[14]), nutritional status (Mini-Nutritional Assessment, MNA[35]), and mobility (Timed up and go[15]). Other patient-reported outcomes (PROs) included anxiety and depression (Hospital Anxiety and Depression Scale, HADS[36]), insomnia (Insomnia Severity Index, ISI[37]), fatigue (FACIT-F[16]), and pain (Visual analogue scale[38]).

Cognitive impairment and decline

Baseline objective cognitive impairment was estimated using the ICCTF criterion[32] (Supplementary information 4). Overall objective cognitive impairment corresponds to impairment in at least two of the six objective domains. During follow-up, objective decline was estimated using a composite reliable change index (RCI), corrected for practice effect. Overall objective cognitive decline corresponds to decline in at least two of the six objective domains.

Subjective cognitive impairment at baseline was defined as ratings ≤ 10th percentile of the norms[39] for PCI and PCA. During follow-up, subjective cognitive decline was defined as a ≥ 10% decrease since baseline[40].

Statistical analyses

To be considered in the analyses, participants had to have completed at least the baseline and the 3-month visits. Between-group differences for participants’ baseline characteristics were examined using the Wilcoxon and Kruskal-Wallis tests for continuous variables, and the χ² or Fisher exact test for categorical variables, as appropriate.

Between-group differences in cognitive functioning were expressed in the following ways: (1) rates of patients with overall objective and subjective cognitive impairment and decline, estimated with the aforementioned criteria, were analyzed using the χ² or Fisher exact test, as appropriate; (2) composite Z-scores in each objective domain (mean Z-scores of the corresponding measures), PCI and PCA scores for subjective cognition were examined with multivariate linear models, adjusted for baseline cognition, age, education, fatigue and previous ADT duration.

Multivariable linear analyses were performed in ADT + ARPI patients to examine the association between baseline characteristics and changes in objective domains and in subjective cognition.

Analyses were performed using R 4.2.1[41]. Statistical tests were two-tailed, and p-values < 0.05 were considered statistically significant.

Data availabity

The data that support the findings of this study are available from the corresponding author upon reasonable request. Additional methods and data are available in the Supplementary information file.

Ethics approval and consent to participate

The COG-PRO study has received ethical approval from the North West III Committee for the Protection of Individuals and from National Agency for Medical and Health products Safety (Reference: 2016–001248-20). All patients gave their informed consent before any study-related assessment was started.

Acknowledgements

This study was supported by a public grant overseen by the French National Institute of Cancer (Institut national du cancer, INCa) as part of the program “Research in Social and Human Sciences, Epidemiology and Public Health” (SHS-E-SP-2015-9528), and by a specific donation from Astellas Pharma. The funders had no role in study design, data collection, data analysis, data interpretation or writing of the report. This study was made possible thanks to the commitment of Giulia Binarelli, Aurélie Capel, Marie Fernette, Chantal Rieux, and Chankannira San. We extend our sincere appreciation to thank all investigators, patients and non-cancer participants.

CRediT authorship contribution statement

Antoine Boué: methodology, formal analysis, investigation, data curation, writing - original draft, visualization. Giulia Baciarello: investigation. Emmanuel Meyer: investigation. François Christy: methodology, formal analysis, data curation, visualization. Nedjla Allouache: investigation. Raffaele Ratta: investigation. Philippe Beuzeboc: investigation. Pierre-Emmanuel Brachet: investigation. Estelle Guerdoux: investigation, writing - review & editing. Amélie Darlix: investigation, writing - review & editing. Mathieu Boone: investigation. Sophie Gouerant: investigation. Alexandra Leconte: conceptualization, project administration. Justine Lequesne: methodology, formal analysis. Bénédicte Clarisse: conceptualization, project administration. Karim Fizazi: investigation, writing - review & editing. Marie Lange: conceptualization, methodology, investigation, writing - review & editing, supervision. Florence Joly: conceptualization, methodology, investigation, writing - review & editing, supervision, funding acquisition.

Declaration of Interest

Statement

Giulia Baciarello: Astellas (advisory board, invited speaker). Emmanuel Meyer: Astellas (invited speaker), Ipsen (invited speaker), Recordati (invited speaker).

Raffaele Ratta: Astellas (invited speaker), AstraZeneca (advisory board), Bristol Meyer Squibb (advisory board), Ipsen (invited speaker), Janssen (advisory board), Merck (advisory board), Novartis (advisory board), Pfizer (advisory board). Estelle Guerdoux: CanceroConsult (invited speaker). Amélie Darlix: Novocure (advisory board), Servier (advisory board). Mathieu Boone: Novocure (invited speaker), Servier (advisory board). Bénédicte Clarisse: Astellas (institutional financial support), Pfizer (institutional financial support, product samples). Karim Fizazi: AAA (advisory board), Arvinas (advisory board), Astellas (advisory board, invited speaker), AstraZeneca (advisory board, invited speaker, research grant, principal investigator), Bayer (advisory board, invited speaker, research grant, principal investigator), BMS (research grant, principal investigator), Clovis (principal investigator), Curevac (advisory board), Daiichi Sankyo (advisory board), Janssen (adivsory board, invited speaker, trial chair, research grant), Macrogenics (advisory board), Merck (principal investigator), MSD (advisory board, invited speaker, research grant), Novartis (invited speaker), Novartis/AAA (advisory board, principal investigator), Orion (advisory board, research grant, principal investigator), Pfizer (advisory board, invited speaker, research grant, principal investigator), Sanofi (invited speaker).

Florence Joly: Amgen (invited speaker), Astellas (advisory board, research grant), AstraZeneca (advisory board, invited speaker, coordinating principal investigator), Bayer (advisory board), BMS (research grant), Chugai (travel and congress), Esai (advisory board, invited speaker, travel), GCIG (member), GSK (advisory board, invited speaker, coordinating principal investigator, travel), Ipsen (advisory board, invited speaker, travel and congress), Janssen (advisory board, invited speaker, research grant, funding), MSD (advisory board, invited speaker, travel and congress), Novartis/AAA (invited speaker), Novocure (advisory board), Pfizer (advisory board), Seagen (Advisory board), Viatris (invited speaker).

Electronic Supplementary Material

Below is the link to the electronic supplementary material

Supplementary Material 1

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Figures and tables

Yes