Degarelix for treating advanced hormone‐sensitive prostate cancer

Friedemann Zengerling<sup>a</sup>; Joachim J Jakob<sup>a</sup>; Stefanie Schmidt; Joerg J Meerpohl; Anette Blümle; Christine Schmucker; Benjamin Mayer; Frank Kunath

doi:10.1002/14651858.CD012548.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 1 Degarelix 240 mg induction dose/80 mg maintenance dose versus standard androgen suppression therapy (GnRH agonists or maximum androgen suppression therapy), outcome: 1.1 Serious adverse events.

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Figure 5

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Figure 6

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Analysis 1.1

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 1: Serious adverse events

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Analysis 1.2

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 2: Quality of life

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Analysis 1.3

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 3: Injection site pain

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Analysis 1.4

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 4: Cardiovascular events

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Analysis 1.5

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 5: Back pain

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Analysis 1.6

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 6: Gynecomastia

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Analysis 1.7

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 7: Constipation

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Analysis 1.8

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 8: Diarrhea

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Analysis 1.9

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 9: Vomiting

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Analysis 1.10

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 10: Loss of sexual interest

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Analysis 1.11

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 11: Loss of sexual function

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Analysis 1.12

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 12: Fatigue

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Analysis 1.13

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 13: Hot flushes

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Analysis 1.14

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 14: Anemia

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Analysis 1.15

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 15: Hepatic enzyme increase (alanine aminotransferase)

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Analysis 1.16

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 16: Dyspnea

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Analysis 1.17

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 17: Urinary tract infection

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Analysis 1.18

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 18: Hematuria

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Analysis 1.19

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 19: Urinary retention

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Analysis 1.20

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 20: Mortality during study conduction (post hoc)

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Analysis 1.21

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 21: Discontinuation due to adverse events (post hoc)

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Analysis 1.22

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 22: Total non‐serious adverse events (post hoc)

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Analysis 1.23

Comparison 1: Degarelix versus standard androgen suppression therapy, Outcome 23: Biochemical progression

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Analysis 2.1

Comparison 2: Degarelix versus androgen suppression therapy (GnRH agonists or maximum androgen suppression therapy): subgroup analysis based on different doses, Outcome 1: Serious adverse events

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Analysis 2.2

Comparison 2: Degarelix versus androgen suppression therapy (GnRH agonists or maximum androgen suppression therapy): subgroup analysis based on different doses, Outcome 2: Quality of life

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Analysis 2.3

Comparison 2: Degarelix versus androgen suppression therapy (GnRH agonists or maximum androgen suppression therapy): subgroup analysis based on different doses, Outcome 3: Injection site pain

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Summary of findings 1. Degarelix compared to standard androgen suppression therapy for treating advanced hormone‐sensitive prostate cancer

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		What happens
Degarelix compared to standard androgen suppression therapy for treating advanced hormone‐sensitive prostate cancer
Patient or population: hormone‐sensitive prostate cancer Setting: outpatient Intervention: degarelix Comparison: standard androgen suppression therapy
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with standard androgen suppression therapy (GnRH agonists or maximum androgen suppression therapy)	Risk difference with degarelix	What happens
Overall survival	‐	‐	‐	‐	N/A	We do not know the effect of degarelix on overall survival.
Serious adverse events Follow‐up: range 1 month to 14 months	2750 (9 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.80 (0.62 to 1.05)	Study population		Degarelix may have little to no effect on serious adverse events.
	2750 (9 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.80 (0.62 to 1.05)	114 per 1000	23 fewer per 1000 (43 fewer to 6 more)
Quality of life assessed with: FACT‐P, EORTC QLQ‐C30, SF‐36 Follow‐up: 14 months	2887 (3 RCTs)	⊕⊕⊕⊝ MODERATE ¹	‐	The mean quality of life was 0.	SMD 0.06 higher (0.05 lower to 0.18 higher)	Degarelix probably has little to no effect on quality of life.
Cancer‐specific survival	‐	‐	‐	‐	N/A	We do not know the effect of degarelix on cancer‐specific survival.
Cardiovascular events Follow‐up: 12 months	80 (1 RCT)	⊕⊕⊝⊝ VERY LOW ^{1 2 3}	RR 0.15 (0.04 to 0.61)	General population⁴		The effect of degarelix on cardiovascular events is very uncertain.
Cardiovascular events Follow‐up: 12 months	80 (1 RCT)	⊕⊕⊝⊝ VERY LOW ^{1 2 3}	RR 0.15 (0.04 to 0.61)	300 per 1000	255 fewer per 1000 (288 fewer to 117 fewer)
Injection site pain Follow‐up: range 1 month to 14 months	2670 (8 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 15.68 (7.41 to 33.17)	Study population		Degarelix probably increases the occurrence of injection site pain.
Injection site pain Follow‐up: range 1 month to 14 months	2670 (8 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 15.68 (7.41 to 33.17)	30 per 1000	440 more per 1000 (192 more to 965 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FACT‐P: Functional Assessment of Cancer Therapy‐Prostate; GnRH: gonadotropin‐releasing hormone; RCT: randomized controlled trial; RR: risk ratio; SMD: standardized mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded by one level for study limitations (performance or detection bias, or both). ²Downgraded by one level for imprecision. ³Downgraded by one level for indirectness, as the Margel 2019 (0102‐15‐RMC) study was based on participants with pre‐existing cardiovascular morbidity (“high risk population”). ⁴The control event rate was taken from Cardwell 2020, which enrolled 20,216 prostate cancer patients from the Scottish Cancer Registry.

Summary of findings 1. Degarelix compared to standard androgen suppression therapy for treating advanced hormone‐sensitive prostate cancer

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Table 1. Baseline characteristics

Study name	Intervention(s) and comparators (s)	Follow‐up	Number of participants	Study dates	Stage of disease
Anderson 2013 (CS28)	Degarelix 240/80 mg¹	12 weeks	27	2009 to 2010	Localized/locally advanced: 9 (22.5%) Metastatic: 14 (35%) Unclear: 17 (42.5%)
Anderson 2013 (CS28)	GnRH agonist with flare protection (goserelin 3.6 mg s.c. every 28 days with bicalutamide 50 mg orally per day for 14 days)	12 weeks	13	2009 to 2010
Axcrona 2012 (CS31)	Degarelix 240/80 mg¹	12 weeks	82	2009 to 2011	Localized: 56 (31%) Advanced: 106 (59%) Unclear: 17 (9%)
Axcrona 2012 (CS31)	GnRH agonist with flare protection (goserelin 3.6 mg s.c. every 28 days with bicalutamide 50 mg orally per day for 28 days)	12 weeks	97	2009 to 2011	Localized: 56 (31%) Advanced: 106 (59%) Unclear: 17 (9%)
Crawford 2013 (CS37)	Degarelix 240/80 mg² (intermittent; data not included)	14 months	175	2009 to 2012	Unclear (not reported)
	Degarelix 240/80 mg¹		50
	GnRH agonist with flare protection (leuprolide 7.5 mg i.m. monthly, maintenance dose 22.5 mg i.m. 3‐monthly with bicalutamide 50 mg orally per day for 28 days on Investigator's discretion)		178
Klotz 2008 (CS21)	Degarelix 240/160 mg (degarelix starting dose of 240 mg s.c. with maintenance doses of 80 mg s.c. every 28 days)	364 days	202	2006 to 2007	Localized: 191 (31%) Locally advanced: 178 (29%) Metastatic: 125 (20%) Not classifiable: 116 (19%)
	Degarelix 240/80 mg¹		207
	GnRH agonist (leuprolide 7.5 mg i.m. monthly)		201
Margel 2019 (0102‐15‐RMC)	Degarelix 240/80 mg s.c.¹	12 months	41	2015 to 2019	Localized: 59 (74%) Metastatic: 21 (26%)
Margel 2019 (0102‐15‐RMC)	GnRH agonist 3‐monthly (at the discretion of the treating urologist/oncologist)	12 months	28	2015 to 2019	Localized: 59 (74%) Metastatic: 21 (26%)
Mason 2013 (CS30)	Degarelix 240/80 mg¹	12 weeks	180	2009 to 2011	Localized: 152 (62%) Advanced: 83 (34%) Unclear: 9 (4%)
Mason 2013 (CS30)	GnRH agonist with flare protection (goserelin 3.6 mg s.c. every 28 days with bicalutamide 50 mg orally per day for 14 days)	12 weeks	64	2009 to 2011	Localized: 152 (62%) Advanced: 83 (34%) Unclear: 9 (4%)
Ozono 2018 (3550‐CL‐0010)	Degarelix 240/480 mg (starting dose of 240 mg s.c. with maintenance doses of 480 mg s.c. every 84 days)	12 months	117	2013 to 2016	Localized: 124 (53%) Locally advanced: 63 (27%) Metastatic: 44 (19%) Unclear: 3 (1%)
Ozono 2018 (3550‐CL‐0010)	GnRH agonist (goserelin 3.6 mg s.c. with maintenance dose 10.8 mg s.c. every 84 days)	12 months	117	2013 to 2016
Sawazaki 2019	Degarelix 240/80 mg¹	6 months	50	2016 to 2018	Localized: 76 (76%) Locally advanced and/or metastatic: 24 (24%)
Sawazaki 2019	GnRH agonist (leuprolide 3.75 mg every 28 days)	6 months	50	2016 to 2018
Sayyid 2017 (DEG_PRE‐OP)	Degarelix 240/80 mg¹	12 weeks	13	2012 to 2015	Localized: 10 (26%) Locally advanced: 15 (60%) Node positive: 6 (24%) PSA failure (> 0.2 ng/mL) or use of adjuvant androgen suppression/radiotherapy: 8 (21%)³
	Degarelix 240/80 mg s.c. 2‐monthly + bicalutamide 50 mg orally per day (data not included)		14
	GnRH agonist + bicalutamide (leuprorelin 22.5 mg, leuprolide 22.5 mg, or goserelin acetate 10.8 mg 3‐monthly and bicalutamide 50 mg orally per day)		12
Shore 2012 (CS35)	Degarelix 240/480 mg (starting dose of 240 mg s.c. with maintenance doses of 480 mg s.c. every 3 months)	13 months	565	2009 to 2011	Unclear (not reported)
Shore 2012 (CS35)	GnRH agonist (goserelin 3.6 mg s.c. with maintenance doses of 10.8 mg s.c. 3‐monthly)	13 months	283	2009 to 2011	Unclear (not reported)
Xie 2016 (PANDA)	Degarelix 240/80 mg¹	364 days	143	2013 to 2015	Unclear (not reported)
Xie 2016 (PANDA)	GnRH agonist (goserelin 3.6 mg s.c. monthly)	364 days	142	2013 to 2015	Unclear (not reported)
Abbreviations: GnRH: gonadotropin‐releasing hormone; i.m.: intramuscular; PSA: prostate‐specific antigen; s.c.: subcutaneous ¹Degarelix starting dose of 240 mg s.c. with maintenance doses of 80 mg s.c. every 28 days. ²Degarelix starting dose of 240 mg s.c. with maintenance doses of 80 mg s.c. every 28 days. Six maintenance doses of degarelix 80 mg per month at Days 28 to 168 were administered. If a participant had PSA ≥ 2 ng/mL at any visit, additional doses of degarelix 240 mg followed by 80 mg maintenance dose(s) were administered. Degarelix treatment provided for first seven months (one starting dose and six maintenance doses) followed by no treatment for next seven‐month period. ³Multiple entries possible.

Table 1. Baseline characteristics

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Comparison 1. Degarelix versus standard androgen suppression therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Serious adverse events Show forest plot	9	2750	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.62, 1.05]

1.2 Quality of life Show forest plot	3	2887	Std. Mean Difference (IV, Random, 95% CI)	0.06 [‐0.05, 0.18]

1.3 Injection site pain Show forest plot	8	2670	Risk Ratio (M‐H, Random, 95% CI)	15.68 [7.41, 33.17]

1.4 Cardiovascular events Show forest plot	1	80	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.04, 0.61]

1.5 Back pain Show forest plot	5	2102	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.46, 0.96]

1.6 Gynecomastia Show forest plot	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.01, 6.94]

1.7 Constipation Show forest plot	4	1112	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.39, 1.46]

1.8 Diarrhea Show forest plot	2	253	Risk Ratio (M‐H, Random, 95% CI)	1.56 [0.47, 5.18]

1.9 Vomiting Show forest plot	2	837	Risk Ratio (M‐H, Random, 95% CI)	1.56 [0.79, 3.08]

1.10 Loss of sexual interest Show forest plot	2	270	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.35, 3.17]

1.11 Loss of sexual function Show forest plot	2	427	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.39, 1.69]

1.12 Fatigue Show forest plot	6	1996	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.60, 1.16]

1.13 Hot flushes Show forest plot	8	2412	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.86, 1.14]

1.14 Anemia Show forest plot	5	1914	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.13, 0.74]

1.15 Hepatic enzyme increase (alanine aminotransferase) Show forest plot	4	1014	Risk Ratio (M‐H, Random, 95% CI)	2.15 [1.26, 3.66]

1.16 Dyspnea Show forest plot	1	182	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.02, 9.41]

1.17 Urinary tract infection Show forest plot	5	1908	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.25, 0.87]

1.18 Hematuria Show forest plot	2	636	Risk Ratio (M‐H, Random, 95% CI)	1.69 [0.58, 4.94]

1.19 Urinary retention Show forest plot	5	1925	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.13, 1.40]

1.20 Mortality during study conduction (post hoc) Show forest plot	4	1821	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.21, 0.97]

1.21 Discontinuation due to adverse events (post hoc) Show forest plot	8	2666	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.79, 1.56]

1.22 Total non‐serious adverse events (post hoc) Show forest plot	8	2412	Risk Ratio (M‐H, Random, 95% CI)	1.08 [1.01, 1.15]

1.23 Biochemical progression Show forest plot	2	691	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.43, 0.87]

Comparison 1. Degarelix versus standard androgen suppression therapy

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Comparison 2. Degarelix versus androgen suppression therapy (GnRH agonists or maximum androgen suppression therapy): subgroup analysis based on different doses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Serious adverse events Show forest plot	9	2951	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.63, 1.03]

2.1.1 Degarelix 240 mg/80 mg	7	1466	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.39, 1.14]
2.1.2 Degarelix 240 mg/160 mg	1	403	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.51, 1.42]
2.1.3 Degarelix 240 mg/480 mg	2	1082	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.64, 1.26]
2.2 Quality of life Show forest plot	3	2887	Std. Mean Difference (IV, Random, 95% CI)	0.06 [‐0.05, 0.18]

2.2.1 Degarelix 240 mg/80 mg	2	2040	Std. Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.33, 0.28]
2.2.2 Degarelix 240 mg/480 mg	1	847	Std. Mean Difference (IV, Random, 95% CI)	0.10 [‐0.04, 0.24]
2.3 Injection site pain Show forest plot	8	2670	Risk Ratio (M‐H, Random, 95% CI)	15.68 [7.41, 33.17]

2.3.1 Degarelix 240 mg/80 mg	6	1286	Risk Ratio (M‐H, Random, 95% CI)	14.94 [4.48, 49.81]
2.3.2 Degarelix 240 mg/160 mg	1	302	Risk Ratio (M‐H, Random, 95% CI)	61.20 [3.82, 979.36]
2.3.3 Degarelix 240 mg/480 mg	2	1082	Risk Ratio (M‐H, Random, 95% CI)	15.24 [8.50, 27.31]

Comparison 2. Degarelix versus androgen suppression therapy (GnRH agonists or maximum androgen suppression therapy): subgroup analysis based on different doses

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