TABLE 3.

Evaluation of HRQoL outcomes/recommendations for included high‐quality PROs

Name of trial	Treatment	HRQoL outcome	Clinical outcome	Treatment recommendations
PREVAIL* Loriot 27 Beer 28 Devlin 29	Enzalutamide (160 mg/d) vs placebo	Enza: reduced risk of and delayed time to HRQoL deterioration, pain progression, and occurrence of SREs.		Enza is recommended in asymptomatic and minimally symptomatic, chemo‐naïve patients with mCRPC due to its positive effects on survival and HRQoL benefits.
			Significant delay in radiographic disease progression or death and need for cytotoxic chemotherapy
		Significant benefits in terms of Pain/Discomfort and Anxiety/Depression (EQ‐5D)
REACTT Patel 30 Montorsi 31	9 mo tadalafil 5 mg once daily vs tadalafil 20 mg on demand vs placebo	Early chronic dosing after nsRP increases and accelerates EF recovery and improves patients’ QoL.		Tadalafil treatment may contribute to the recovery of EF after RP
		Improvements in IIEF‐EF and successful intercourse during 9 mo tadalafil once daily were not sustained 6w after drug cessation.	Protection from penile length loss
RTOG‐0126* Bruner 32 Michalski 33 Michalski 34	3D‐CRT vs IMRT	No difference in patient‐reported bowel, bladder, or sexual functions		The decision to deliver high radiation dose must be balanced against the risk of morbidity in the individual patient.
		IMRT: Lower incidence of acute GI or GU toxicity and a lower cumulative incidence of late grade 2b rectal toxicity
		Increase in late grade 2 or greater GI and GU toxic effects.	Improvement in biochemical failure and distant metastases, but no improvement in OS.
AFFIRM* Fizazi 35 Cella 36 Scher 37 Armstrong 38	Enzalutamide (160 mg/d) vs placebo	Reduction of the risk of SREs. Reduction of pain and increase in time to HRQoL deterioration		Enza improves both OS and well‐being and everyday functioning of patients with mCRPC (postchemo)
		Stabilization of patient HRQoL
			Prolonged OS
			PSA declines of any, ≥30%, and ≥50% within 90 d of Enza were strongly associated with the clinical benefit
COU‐AA‐302 phase 3* Basch 39 Ryan 40	Abiraterone acetate + prednisone vs prednisone alone	Delay in patient‐reported pain progression and HRQoL deterioration		Abi + prednisone can be recommended for patients with mCRPC (prechemo)
			Improvement of radiographic PFS, a trend toward improvement of OS, and significant delay in clinical decline and initiation of chemotherapy
PROTECT Beer 41 Beer 42	Sipuleucel‐T vs placebo	No clinically significant negative impact on QoL		Long‐term FU is needed to determine the effect on clinically important events
			No difference in biochemical failure
SWOG‐9346, 2013* Hussain 43	Intermittent vs continuous ADT	Intermittent therapy was associated with improved EF and mental health at 3 mo but not thereafter.	Too few events occurred to rule out significant inferiority of intermittent therapy	In this noninferiority trial, findings were statistically inconclusive
NR Mason 44	Degarelix + RT vs Goserelin with bicalutamide + RT	Degarelix had more pronounced effects on LUTS in symptomatic patients	Noninferior efficacy of degarelix in terms of prostate shrinkage	Degarelix provides an alternative treatment for PCa patients who need neoadjuvant ADT before RT, especially for those having LUTS problems.
TROG 03.04 RADAR Denham 18 Denham 45 Denham 46	STAS (6 mo) vs STAS + ZA vs ITAS (12 mo) vs ITAS + ZA	ITAS + RT causes adverse effects on some PROs but not on global QoL scores. Only hormone treatment‐related symptoms persisted at marginally higher frequencies. HDR‐BT boost adversely affected emotional function and financial problems.		Further follow‐up of the RADAR trial is needed before we can take our findings to the clinic
			No difference in PCa‐specific mortality between the 4 groups
		ADT, ZA and increasing EBRT dose did not increase rectal or urinary dysfunction. The use of HDR‐BT increased urinary dysfunction.
NCT00884273 Axcrona 47	12 wk of degarelix (240/80 mg) vs goserelin (3.6 mg) + 28 d of bicalutamide.	Degarelix showed superiority in LUTS relief in symptomatic patients	Same reduction in total prostate volume	Degarelix can be considered as a useful approach to combined GnRH agonist plus antiandrogen for PCa patients in need of short‐term neoadjuvant ADT.
CHHiP* Wilkins 17 Dearnaley 48	Hypofractionated RT vs conventional RT	PROs were not significantly different between treatment groups for any of the endpoints		Hypofractionated RT using 60 Gy in 20 fractions is recommended as new standard of care for EBRT of localized PCa.
			Hypofractionated schedule is noninferior to the conventionally fractionated schedule for time to biochemical or clinical failure
ACTRN12611000661976* Yaxley 15	RARP vs RRP	No difference in domain‐specific QoL outcomes at 12 wk	No difference in pathological outcomes at 12 wk	Long‐term follow‐up is needed
NCT00866554 Gaudet 49	Dutasteride 0.5 mg + Bicalutamide 50 mg + Tamoxifen 10 mg daily vs LHRH agonist + Bicalutamide daily	Less sexual toxicity compared to LHRH agonists prior to BT and for the first 6 mo after BT	Noninferior efficacy to LHRH agonist based regimens for prostate volume reduction prior to BT	D + B is therefore an option to be considered for prostate volume reduction prior to BT
TROG 03.06 and VCOG PR 01‐03* Duchesne 50 G Dushesne 51	Immediate vs delayed ADT (PSA relapse only)	Early detriments in specific hormone treatment‐related symptoms with immediate ADT, but with no other demonstrable effect on overall functioning or HRQoL		Progression is delayed, but at a small cost in global QoL. The option can be discussed with men with a PSA relapse.
			Immediate receipt of ADT significantly improved OS
MRC PATCH trial (PR09) Gilbert 52 Langley 53 RE Langley 54	Transdermal estradiol vs LHRH agonist	estradiol: better self‐reported QoL outcomes at 6 mo but increased gynecomastia		Provides further supporting evidence for the ongoing phase 3 trial
			Castrate testosterone concentrations similar to those achieved with LHRHa
		Mitigating BMD loss	Castration levels of testosterone comparable with LHRHa administration
ASCENDE‐RT trial* Rodda 55 Morris 56	LDR‐BT vs DE‐EBRT	LDR‐PB boost: more moderate to severe GU toxicity, urinary incontinence, and need for catheterization and a larger mean decline in HRQoL for physical and urinary function at 6 y.		Treatment should be individualized and requires careful consideration of the potential risks and benefits.
			LDR‐PB patients were twice as likely to be free of BF at a median follow‐up of 6.5 y
PROSPER* Hussain 57 Tombal 58	Enzalutamide vs placebo		Significantly increased metastasis‐free survival	Enza is a treatment option that should be discussed in high‐risk, nmCRPC
		Benefit in delaying pain progression, symptom worsening, and decrease in functional status
RTOG 0938, 2018 Lukka 59	Two ultrahypofractionated RT schemes	Both schemes are well tolerated and bowel, urinary, and sexual PROs are comparable to those for standard RT		Longer follow‐up is required
COMET‐2, 2018 Basch 60	Cabozantinib vs mitoxantrone‐prednisone	Cabozantinib treatment did not improve pain palliation		Enrollment was terminated
SPARTAN* Saad 16 MR Smith 61	Apalutamide vs placebo	HRQoL was maintained after initiation of apalutamide treatment		Apalutamide provides clinical benefit in the treatment of men with nmCRPC
			Metastasis‐free survival and time to symptomatic progression were significantly longer
NCT 02135357 Khalaf 62 Annala 63	Abiraterone vs enzalutamide	PROs favored Abi with differences in FACT‐P and PHQ‐9 scores. Differences in the total FACT‐P score only in the elderly subgroup.		Abi and Enza are standard first‐line treatment options for mCRPC with similar efficacy but different side‐effect profiles. Administration should be discussed with each patient individually.
			Enza: superior PSA responses but no differences in progression‐free survival
CHAARTED* Sweeney 66 Morgans 67	ADT + Docetaxel vs ADT alone		Six cycles of docetaxel at the beginning of ADT resulted in significantly OS than ADT alone.	For patients with hormone‐sensitive metastatic PCa, who are fit enough ADT + docetaxel can be considered
		Both arms reported a similar minimally changed QoL over time, suggesting that ADT + Docetaxel is not associated with a greater long‐term negative impact on QoL
LATITUDE* Fizazi 68 Chi 69	ADT + abiraterone acetate + prednisone vs ADT alone		Addition of abiraterone acetate increased OS and radiographic progression‐free survival	Treatment with ADT plus abiraterone acetate and prednisone could be considered a new option for standard of care for patients with metastatic castration‐naïve PCa
		Addition of abiraterone acetate improved overall PROs by consistently showing a clinical benefit in the progression of pain, PCa symptoms, fatigue, functional decline, and overall HRQoL.
SWOG S0421 Unger 64 Quinn 65	Docetaxel + Atrasentan vs Docetaxel + placebo	No substantial treatment arm differences for pain and functional status		Docetaxel remains one of the standard options for CRPC. Endothelin inhibitors do not have an established role.
			Atrasentan did not improve PFS or OS