Supplementary data: Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer

Table 2.

Retrospective studies of androgen-deprivation therapy outcomes by testosterone level

Study type N Setting	ADT regimen(s)	T level	Time to PSA progression (months)	PFS (months) HR (95% CI)	OS (months) HR (95% CI) or (range)	Other results
Pickles 201231 Database review 2196 L, LA	Curative RT Adjuvant LHRHA therapy	>1.1 nmol/la	NR	NR	NR	Rate of T breakthroughb with increase to >1.1 nmol/l was 6.6% per patient course and 5.4% per LHRHA injection, and rate with increase to >1.7 nmol/l was 3.4% per patient course and 2.2% per LHRHA injection. Repeated breakthroughs occurred in 16% of patients. Younger men were more liable to breakthroughs (p<0.001). Early PSA kinetic surrogates of cancer control were inferior in those with breakthroughs. Post-treatment PSA nadir was also higher in those with breakthroughs: 0.02 ng/ml for those without a breakthrough, compared with 0.04 ng/ml for testosterone >1.1 nmol/l or >1.7 nmol/l (p=0.008 and p=0.003, respectively).
		>1.7 nmol/la
Kamada 201526 Multicentre 225 L, LA & Met	CAB with LHRH agonists (leuprorelin goserelin), LHRH antagonists (degarelix) or surgical castration and antiandrogensc	<0.7 nmol/ld	NR	16.3  p=0.1163e	68.3 p<0.0014e	For OS on univariate analysis, NT <0.6 nmol/l (p=0.0190), <0.7 nmol/l (p=0.0020), and <1.1 nmol/l (p=0.0146) were significant together with other clinical factors. NT <0.3 and <0.4 nmol/l were not significant. Multivariate analysis showed that NT <0.7 nmol/l was a significant prognostic and predictive factor for OS (p=0.0048). NT <0.7 nmol/l showed the most significant difference for OS (p<0.0001) compared to NT at 6 mos <0.7 nmol/l (p=0.0479) or NT <0.3 nmol/l (p=0.1031).
		≥0.7 nmol/ld		11.0	28.3
Perachino 201028 Single-centre 129 Met	Goserelin 10.8 mg every 12 wks	1.4 nmol/l (6 mo mean)	NR	NR	NR (CSS) 1.333 (1.053–1.687) (p<0.05)f	Higher T level at 6 mos increases the risk of death by 1.33 times (95% CI 1.053–1.687). There was a continuous relationship between testosterone level and CSS: the pretreatment Gleason score and 6-mo PSA level being equal, the lower the 6-mo testosterone level, the longer the survival.
Shiota 201624 Single-centre 96 LA & Met	Surgical castration or medical castration using a LHRH agonist (goserelin acetate or leuprorelin acetate) and/or antiandrogen (bicalutamide, flutamide or chlormadinone acetate) continuously	0.1 nmol/l (2.0–4.0 ng/dl)g (Q1; n=24)	NR	NR p=0.70	95.4h p=0.014i	ST levels were significantly associated with OS, but not PFS (univariate analysis). For survival rate from progression, the ST Q1 group had better prognosis, compared with that of the Q2, Q3, and Q4 groups (p=0.037) and the Q2–Q4 group (p=0.0044).
		0.1–2.6 nmol/l (4.3–76 ng/dl)g (Q2–4; n=72)		NR	NR
Morote 200730 Single-centre 73j L, LA	LHRHA every 3 mos Bicalutamide 50 mg/day 2 wks prior to first LHRHA administration	All measurements <0.7 nmol/l (n=32)	NR	106k	NR	Rates of T breakthroughb with T level 0.7–1.7 nmol/l were observed in 31.5% of patients, and increases >1.7 nmol/l were observed in the remaining 24.7%. The lowest serum T threshold with clinical impact was 1.1 nmol/l; p=0.0258. Patients with all 3 determinations of serum T <1.1 nmol/l had a mean survival free of androgen-independent progression of 137 mos vs. 88 mos for those with any breakthrough increase >1.1 nmol/l; p<0.03.
		Any increase between 0.7–1.7 nmol/l (n=23)		90k
		Any increase >1.7 nmol/l (n=18)		72k
Yasuda 201525 Retrospective 69 Met	LHRHAs leuprolide acetate (n=28) or goserelin acetate (n=41) Bicalutamide 80 mg/ day 2 wks before first LHRHA administration, and continued with CAB therapy	<0.7 nmol/ll (n=57)	15.5h p=0.66	NR	NYR p=0.17 NYR (CSS) p=0.29	No threshold (0. 5, 0.7, or 1.1 nmol/l) of median T level showed a significant relation with TTP, CSS, or OS. Mean maximum T level of each patient during treatment was 0.7 nmol/l (median 0.6 nmol/l). Mean minimum T level of each patient during treatment was 0.4 nnmol/l (median 0.4 nmol/l).

^aBreakthrough level;

^bincrease in serum T >0.7 nmol/l was considered a breakthrough response;

^cbicalutamide, flutamide, or chlormadinone;

^dnadir;

^eWilcox on signed rank test;

^fcontinuous relationship between testosterone level and CSS; increased risk of death with higher testosterone level at 6 mos;

^gmean;

^hestimated from plot;

ⁱST Q1 showed improved OS vs. ST Q2–4;

^j28 patients continued treatment with bicalutamide for maximal androgen blockade;

^kmean androgen-independent progression-free survival;

^lmedian. ADT: androgen-deprivation therapy; CAB: combined androgen blockade; CI: confidence interval; CSS: cause (cancer)-specific survival; HR: hazard ratio; L: localized; LA: locally advanced; LHRH(A): luteinizing hormone-releasing hormone (agonist); Met: metastatic; mo(s): month(s); N or n: number of patients; NR: not reported; NT: nadir testosterone; NYR: not yet reached; OS: overall survival; PFS: progression-free survival; PSA: prostate-specific antigen; QX: quartile X; RT: radiotherapy; ST: serum testosterone; T: testosterone; TTP: time to progression; wk(s): weeks.