Androgen deprivation therapy, comorbidity, cancer stage and mortality from COVID-19 in men with prostate cancer

Figures & data

Table 1. Characteristics of men with prevalent prostate cancer who died from COVID-19 (cases), and their matched controls in PCBaSe RAPID 2019.

	Cases	Controls
	(N = 474)	(N = 23,700)
Characteristics at the time of prostate cancer diagnosis
Age (years), median (IQR)	74 (51 − 94)	67 (35 − 97)
Local clinical tumor stage at prostate cancer diagnosis, % (n)
Localized (T1–T2)	77 (366)	88 (20,859)
Locally advanced (T3–T4)	20 (95)	10 (2,316)
TX	3 (13)	2 (525)
N0	21 (99)	29 (6,811)
N1	2 (11)	2 (583)
NX	77 (364)	69 (16,306)
M0^a	95 (448)	97 (22,904)
M1	5 (26)	3 (796)
PSA at prostate cancer diagnosis (µg/L), median (IQR)	12.0 (7.0 − 25.0)	7.3 (4.9 − 12.4)
Missing, % (n)	4 (17)	2 (463)
Gleason score at prostate cancer diagnosis, % (n)
2–6	31 (148)	48 (11,374)
7 (3 + 4)	25 (118)	25 (5850)
7 (4 + 3)	15 (73)	11 (2676)
8	9 (43)	6 (1,489)
9–10	10 (49)	6 (1,530)
Missing^b	9 (43)	3 (781)
Primary treatment, % (n)
Deferred treatment^c	33 (155)	32 (7,550)
Radical prostatectomy	13 (61)	34 (8,079)
Radical radiotherapy	18 (86)	20 (4,637)
Bicalutamide	10 (46)	4 (862)
GnRH	19 (92)	6 (1362)
Orchidectomy	1 (5)	0.3 (70)
Missing^d	6 (29)	5 (1140)
Any curative treatment, % (n)
Yes	38 (182)	65 (15,459)
Missing	4 (18)	2 (506)
Characteristics on the index date of the study (case date of death)
Age (years), median (IQR)	85 (80 − 89)	75 (69 − 80)
Time (years) since prostate cancer diagnosis, median (IQR)	10.4 (5.8 − 14.8)	6.8 (3.5 − 11.5)
Androgen deprivation therapy, % (n)
None	43 (203)	78 (18,519)
Bicalutamide	16 (76)	10 (2283)
GnRH agonists/antagonists	38 (180)	10 (2423)
Abiraterone/enzalutamide	3 (15)	2 (475)
Duration of ADT (years), median (IQR)	6.2 (3.0 − 10.1)	4.3 (2.0 − 8.3)
Charlson comorbidity index, % (n)
0	18 (83)	62 (14,749)
1–2	42 (199)	27 (6,493)
3–5	31 (145)	9 (2,160)
≥6	10 (47)	1 (298)
Drug Comorbidity Index, median (IQR)	4.4 (2.8 − 6.3)	1.0 (0.2 − 2.4)
History of myocardial infarction, % (n)	20 (93)	9 (2,091)
History of diabetes mellitus, % (n)	26 (122)	10 (2336)
History of COPD, % (n)	14 (66)	5 (1254)
Number of diagnostic codes for specialist outpatient visits during the previous 2 years, median (IQR)	2 (1 − 4)	1 (0 − 3)
Number of days in hospital during the previous 2 years, median (IQR)	12 (2 − 27)	0 (0 − 1)
Fracture, % (n)	14 (66)	3 (734)
Prescribed opioid, % (n)	34 (163)	10 (2325)
Prescribed systemic corticosteroid, % (n)	19 (89)	8 (1836)
Diagnosis indicating metastatic disease, % (n)	10 (49)	5 (1111)

The characteristics were determined at the time of prostate cancer diagnosis or at the index date.

^aAlso includes men categorized as MX.

^bAlso includes cases categorized as 7 without specification.

^cIncludes active surveillance, watchful waiting, and a previously used category for unspecified conservative treatment.

^dAlso includes unspecified curative and non-curative treatment.

ADT: androgen deprivation therapy; COPD: chronic obstructive pulmonary disease; GnRH: Gonadotropin-releasing hormone; IQR: inter-quartile range (25^th to 75^th percentile); PCBaSe: Prostate Cancer data Base Sweden; PSA: prostate-specific antigen.

Figure 1. Forest plot of associations between exposure to any ADT and COVID-19 mortality. Estimated odds ratios are represented by squares and 95% confidence intervals are represented by horizontal whiskers (variables adjusted for in each step are described in the methods section and in Table 2 footnotes). GnRH: gonadotropin-releasing hormone

Table 2. Odds ratios (ORs) with 95% confidence intervals (CIs) for the association between ADT exposure and COVID-19 death (underlying or contributing cause) in men with prostate cancer in PCBaSe RAPID 2019.

Exposure	Cases (N = 459)	Controls (N = 22,497)	Crude OR (95% CI)	Adjusted OR (95% CI) [Model 1: Age]	Adjusted OR (95% CI) [Model 2: Model 1 + Comorbidity^b]	Adjusted OR (95% CI) [Model 3: Model 2 + Prostate cancer risk factors at time of diagnosis^c]	Adjusted OR (95% CI) [Model 4: Model 3 + Indicators of disease progression^d]
No ADT	203	17,929	1.0 (ref)	1.0 (ref)	1.0 (ref)	1.0 (ref)	1.0 (ref)
Any ADT	256	4,568	5.05 (4.18, 6.10)	2.00 (1.63, 2.46)	1.53 (1.22, 1.91)	1.39 (1.05, 1.82)	1.25 (0.95, 1.65)
Bicalutamide	76	2,214	3.07 (2.35, 4.03)	1.39 (1.05, 1.83)	1.20 (0.89, 1.62)	1.08 (0.77, 1.50)	1.03 (0.74, 1.45)
GnRH^a	180	2,354	6.93 (5.63, 8.53)	2.54 (2.02, 3.19)	1.77 (1.38, 2.27)	1.72 (1.26, 2.35)	1.49 (1.08, 2.06)

^aIncludes men on GnRH analogs, GnRH antagonists, and men who underwent orchidectomy.

^bCharlson Comorbidity Index + Drug Comorbidity Index + history of myocardial infarction, diabetes mellitus, COPD + number of days hospitalized + number of outpatient visits.

^cLocal clinical tumor stage at diagnosis + Gleason score (2–6, 7[3 + 4], 7[4 + 3], 8, 9–10) + PSA + any curative treatment.

^dYears since prostate cancer diagnosis + hip/spine fracture or pathological fracture + opioid usage + systemic corticosteroid use + hospital discharge diagnoses indicating metastatic disease.

ADT: androgen deprivation therapy; CI: confidence interval; COPD: chronic obstructive pulmonary disease; GnRH: gonadotropin-releasing hormone; PCBaSe: Prostate Cancer data Base Sweden.

Table 3. Sensitivity analyses: odds ratios (ORs) with 95% confidence intervals (CIs) for the association between ADT exposure and COVID-19 death in men with prostate cancer in PCBaSe RAPID 2019.

Exposure	Cases (N)	Controls (N)	Crude OR (95% CI)	Adjusted OR (95% CI) [model 1: age]	Adjusted OR (95% CI) [Model 2: Model 1 + Comorbidity^b]	Adjusted OR (95% CI) [Model 3: Model 2 + Prostate cancer risk factors at time of diagnosis^c]	Adjusted OR (95% CI) [Model 4: Model 3 + Indicators of disease progression^d]
Restricted to cases with COVID-19 as underlying cause of death^1
No ADT	189	16,153	1.0 (ref)	1.0 (ref)	1.0 (ref)	1.0 (ref)	1.0 (ref)
Any ADT	224	4,090	4.77 (3.91, 5.82)	1.86 (1.50, 2.31)	1.45 (1.15, 1.83)	1.30 (0.98, 1.75)	1.24 (0.92, 1.66)
Bicalutamide	69	1,969	3.04 (2.29, 4.03)	1.33 (0.99, 1.79)	1.19 (0.87, 1.63)	1.06 (0.75, 1.51)	1.05 (0.74, 1.49)
GnRH	155	2,121	6.39 (5.13, 7.97)	2.31 (1.81, 2.94)	1.63 (1.26, 2.13)	1.57 (1.12, 2.18)	1.46 (1.04, 2.05)
Restricted to regions with exposure to GnRH agonists in The Prescription Register^2
No ADT	192	16,365	1.0 (ref)	1.0 (ref)	1.0 (ref)	1.0 (ref)	1.0 (ref)
Any ADT	224	4,044	4.80 (3.94, 5.85)	1.87 (1.51, 2.32)	1.46 (1.16, 1.84)	1.32 (0.99, 1.76)	1.18 (0.88, 1.58)
Bicalutamide	55	1,883	2.52 (1.86, 3.42)	1.10 (0.80, 1.51)	0.95 (0.67, 1.33)	0.86 (0.59, 1.24)	0.83 (0.57, 1.20)
GnRH	169	2,161	6.84 (5.52, 8.47)	2.51 (1.98, 3.17)	1.82 (1.41, 2.35)	1.79 (1.30, 2.46)	1.56 (1.12, 2.17)

^aIncludes men on GnRH agonists and antagonists, and men who underwent orchidectomy.

^bCharlson Comorbidity Index + Drug Comorbidity Index + history of myocardial infarction, diabetes mellitus, COPD + number of days hospitalized + number of outpatient visits.

^cLocal clinical tumour stage at diagnosis + Gleason score (2–6, 7[3 + 4], 7[4 + 3], 8, 9–10) + PSA + any curative treatment.

^dYears since prostate cancer diagnosis + hip/spine fracture or pathological fracture + opioid usage + systemic corticosteroid usage + hospital discharge diagnoses indicating metastatic disease.

ADT: androgen deprivation therapy; CI: confidence interval; COPD: chronic obstructive pulmonary disease; GnRH: gonadotropin-releasing hormone; PCBaSe: Prostate Cancer data Base Sweden.

Figure 2. Quantitative evaluation of impact of potential residual confounding. Interpolation of regression coefficients based on the change from the crude estimate to the maximally adjusted estimate. The curve describes the relation between percent adjustment of confounding and the resulting completely adjusted odds ratio (causal effect). The calculation is based on the maximally adjusted odds ratio from the main analysis (the intercept). OR: odds ratio

Data availability statement

Data used in the present study was extracted from the Prostate Cancer Database Sweden (PCBaSe), which is based on the National Prostate Cancer Register (NPCR) of Sweden and linkage to several national health-data registers. The data cannot be shared publicly because the individual-level data contain potentially identifying and sensitive patient information and cannot be published due to legislation and ethical approval (https://etikprovningsmyndigheten.se). Use of the data from national health-data registers is further restricted by the Swedish Board of Health and Welfare (https://www.socialstyrelsen.se/en/) and Statistics Sweden (https://www.scb.se/en/) which are Government Agencies providing access to the linked healthcare registers. The data will be shared on reasonable request in an application made to any of the steering groups of NPCR and PCBaSe. For detailed information, please see www.npcr.se/in-english, where registration forms, manuals, and annual reports from NPCR are available alongside a full list of publications from PCBaSe. The statistical program code used for the present study analyses can be provided on request (contact [email protected]).