. 2019 Jun 21;9:510. doi: 10.3389/fonc.2019.00510

Table 2.

Overcoming resistance to endocrine therapy.

Trial/ Phase	Intervention Comparison	T#	# pt	Pt characteristics			Disease characteristics		Previous therapy		Survival
				Age	Menopausal status
					Pre meno	Post meno	HR +ve	HER2 –ve	Chemo	Endocrine	OS	PFS or TTP	CBR	ORR
INHIBITORS OF CYCLIN-DEPENDENT KINASES 4 AND 6
Finn et al. (86)	Palbociclib + letrozole	1	444	62	0	100	100	100	48	56.1	NR	24.8	84.9	42.1
Phase 3	Placebo + letrozole		222	61	0	100	100	100	49.1	56.8	NR	14.5	70.3	34.7
	p											<0.001	<0.001	0.06
Cristofanilli et al. (87)	Fulvestrant + palbociclib	=>2	347	57	21	79	100	100	40	100	34.9	9.5	67	19
Phase 3	Fulvestrant + placebo		174	56	21	79	100	100	43	100	28	4.6	40	9
	p										0.09	<0.0001	<0.0001	0.0019
Hortobagyi et al. (88)	Ribociclib plus letrozole	1	334	62	0	100	100	100	43.7	52.4	NR	25.3	79.9	42.5
Phase 3	placebo plus letrozole		334	63	0	100	100	100	43.4	51.2	33	16	73.1	28.7
	p											9.63 × 10⁻⁸	NS	9.18 × 10⁻⁵
Slamon et al. (89)	Ribociclib + Fulvestrant	=>1	484	63	0	100	100	100	A43.2,N13.4∧	48.8	NR	20.5	70.2	32.4
Phase 3	Placebo + fulvestrant		242	63	0	100	100	100	A41.7,N12.4∧	45	NR	12.8	62.8	21.5
	p											<0.001	0.02	<0.001
Tripathy et al. (90) Phase 3	Ribociclib + ET	=>1	335	43	100	0	100	100	55	38	NR	23.8	79	41
	Placebo + ET		337	45	100	0	100	100	55	42	NR	13	70	30
	p											<0.0001	0.0020	0.00098
Sledge et al. (91)	Abemaciclib + fulvestrant	2	446	59	16.1	83.2	100	100	59.9	100	NR	16.3	72.2	35.2
Phase 3	Placebo + fulvestrant		223	62	18.8	80.7	100	100	60.1	100	NR	9.3	56.1	16.1
	p											<0.001	<0.001	<0.001
Goetz et al. (92)	Abemaciclib + NSAI	1	328	63	0	100	100	100	38.1	45.7	NR	NR	78	48.2
Phase 3	Placebo + NSAI		165	63	0	100	100	100	40	49.5	NR	14.7	71.5	34.5
	p											0.000021	0.101	0.002
INHIBITORS OF MAMMALIAN TARGET OF RAPAMYCIN
Yardley et al. (93)	Everolimus + exemestane	2	485	62	0	100	100	100	69	84	31	7.8	51.3	12.6
Phase 3	Exemestane + placebo		239	61	0	100	100	100	65	84	26.6	3.2	26.4	1.7
	p										0.1426	<0.0001	<0.0001	<0.0001
Wolff et al. (94)	Letrozole + temsirolimus	1	555	63	0	100	96	40	65	43	NR	8.9	NR	27
Phase 3	Letrozole + placebo		555	63	0	100	95	47	59	40	NR	9	NR	27
	p											0.25		NS
Bachelot et al. (95)	Tamoxifen + everolimus	2	54	63	0	100	100	98	70	100	NR	TTP, 8.6	61	NR
Phase 2	Tamoxifen		57	66	0	100	100	93	82	100	32.9	4.5	42	NR
	p										<0.05	<0.05	<0.05
PI3K INHIBITORS
Baselga et al. (96)	Buparlisib + fulvestrant	=>2	576	62	0	100	100	100	24	100	33.2	6.9	43.8	11.8
Phase 3	Placebo + fulvestrant		571	61	0	100	100	100	31	99	30.4	5	42	7.7
	p										NS	0.00021	NS	NS
Baselga et al. (97)	Buparlisib plus fulvestrant	=>2	289	60	0	100	100	100	36	100	NR	3.9	71	8
Phase 3	Placebo plus fulvestrant		143	62	0	100	100	100	35	100	NR	1.8	22	2
	p											0.0003	NS	NS
Baselga et al. (98)	Taselisib + fulvestrant	=>2	417	60	0	100	100	100	NR	100	26.8	7.4	51.5	28
Phase 3	Placebo + fulvestrant		214	61	0	100	100	100	NR	100	23.6	5.4	37.3	11.9
	p										0.85	NS		0.0002
André et al. (99)	Alpelisib + fulvestrant	=>2	NR	NR	0	100	100	100	NR	100	NR	11	NR	36
Phase 3	Placebo + fulvestrant		NR	NR	0	100	100	100	NR	100	NR	5.7	NR	16
	p											0.00065		0.0002
HISTONE DEACYTELASE INHIBITORS
Yardley et al. (100)	Exemestane + entinostat	2	64	63	0	100	98	92	58	100	28.1	4.28	28.1	6.3
Phase 2	Exemestane + placebo		66	62	0	100	98	89	67	100	19.8	2.27	25.8	4.6
	p										0.036	0.055	0.78	0.58
Jiang et al. (101)	Chidamide + exemestane	2	244	NR	0	100	100	100	NR	100	NR	7.4	46.7	18.4
Phase 3	placebo + exemestane		122	NR	0	100	100	100	NR	100	NR	3.8	35.5	9.1
	p											0.0336	0.034	0.026
ANTI-ANGIOGENIC AGENTS
Gray et al. (102)	paclitaxel + bevacizumab	1	368	56	NR	NR	60.6	92.5	66.3	90.8	26.7	11.3	NR	48.9
Phase 3	paclitaxel		354	55	NR	NR	63	89.9	65.3	89.3	25.2	5.9	NR	22.2
	p										0.16	<0.0001		<0.0001
Pivot et al. (103) Phase 3	docetaxel + bevacizumab_7.5	1	248	54	NR	NR	78	100	65	85	30.8	9	NR	55.2
	docetaxel + bevacizumab₁₅		247	55	NR	NR	76	100	68	77	30.2	10.1	NR	64.1
	docetaxel + placebo		241	55	NR	NR	78	100	65	88	31.9	8.2	NR	46.4
	p										NS	0.12,0.006		0.07,0.001
Martin et al. (104)	ET + bevacizumab₁₅	1	190	64	0	100	100	100	43.7	52.6	52.1	19.3	76.8	40.8
Phase 3	ET		184	66	0	100	100	100	47.8	51.6	51.8	14.4	67.4	21.9
	p										0.518	0.126	0.041	<0.001
PROTEASOME INHIBITORS
Adelson et al. (105)	Fulvestrant alone	2	59	57	0	100	100	100	27	66^*	NR	2.69	NR	NR
Phase 2	Fulvestrant + bortezomib		57	59	0	100	100	100	30	30^*	NR	2.73	NR	NR
	p											0.06

T#, Treatment line; # pt, Number of patients; OS, Overall survival; PFS, Progression free survival; TTP, Time to progression; CBR, Clinical benefit rate; ORR, Objective response rate; NR, Not reported; NS, Not significant;

Rate of Endocrine therapy used for metastatic disease; ^A, Adjuvant; N, Neoadjuvant.