COMET-1: Study of Cabozantinib (XL184) Versus Prednisone in Men With Metastatic Castration-resistant Prostate Cancer Previously Treated With Docetaxel and Abiraterone or MDV3100

• Sponsor: Exelixis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01605227
• Collaborator: (none)
• Enrollment: 1,028
• Locations: 264
• Arms: 2
• Duration (Months): 32
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will evaluate the effect of cabozantinib compared to prednisone on overall survival in men with previously treated metastatic castration-resistant prostate cancer with bone-dominant disease who have experienced disease progression on docetaxel-containing chemotherapy and abiraterone or MDV3100.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer; Castration Resistant Prostate Cancer; Pain; Prostatic Neoplasms	Drug: cabozantinib; Drug: prednisone	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1028 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-blind, Controlled Study of Cabozantinib (XL184) Versus Prednisone in Metastatic Castration-resistant Prostate Cancer Patients Who Have Received Prior Docetaxel and Prior Abiraterone or MDV3100
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: cabozantinib Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules.	Drug: cabozantinib; Tablets taken orally once-daily; Other Names: XL184
Active Comparator: prednisone Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib.	Drug: prednisone; Taken twice a day orally. Commercially-obtained prednisone tablets will be over-encapsulated in order to blind identity.

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [OS was measured from the time of randomization until 614 events, approximately 24 months after study start]

   The primary analysis of OS is defined as the time from randomization to death due to any cause. Participants that had not died or were permanently lost to follow-up were censored at the last known date alive. Median OS was calculated using Kaplan-Meier estimates. Analysis for OS was performed after 614 events had occurred.

Secondary Outcome Measures

1. Bone Scan Response (BSR) [BSR was measured at the end of Week 12 as determined by the IRF]

   BSR is defined as >=30% reduction in the bone scan lesion area (BSLA) compared with baseline. Confirmation of bone scan was not required for response or progression. Bone scans were evaluated by an independent radiology facility (IRF) for response.

Other Outcome Measures

1. Progression-free Survival (PFS) [Duration of PFS was defined as time from the date of randomization to earlier of date of radiographic progression (bone/andor soft tissue) according to the investigator's assessment or death, assessed for up to approximately 24 months]

   The exploratory analysis of PFS is the time from randomization to date of first documented radiographic progression (bone and/or soft tissue) according to the investigator's assessment or death. PFS was defined per mRECIST 1.1 and included evaluation of measurable, nonmeasurable, target and nontarget lesions. A Kaplan-Meier analysis was performed to estimate the median duration.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histological or cytological diagnosis of castration resistant prostate cancer (serum testosterone less than 50 ng/dL).

• Evidence of bone metastasis related to prostate cancer on bone scans.

• Received prior docetaxel (minimum cumulative dose of 225 mg/m2) and either abiraterone or MDV3100 treatment and has evidence of prostate cancer progression on each agent independently.

• Maintenance of LHRH agonist or antagonist unless treated with orchiectomy.

• Recovered from toxicities related to any prior treatments, unless the toxicities are clinically non significant or easily manageable.

• Adequate organ and marrow function.

• Capable of understanding and complying with the protocol requirements and signed the informed consent form.

• Sexually active fertile patients and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.

Exclusion Criteria:

• Prior treatment with cabozantinib.

• Treatment with docetaxel, abiraterone, or MDV3100 in the last 2 weeks; or with any other type of cytotoxic or investigational anticancer agent in the last 2 weeks.

• Radiation within 4 weeks (excluded if to mediastinum) or radionuclide treatment within 6 weeks of randomization.

• Known brain metastases or cranial epidural disease.

• Requires concomitant treatment, in therapeutic doses, with anticoagulants.

• Requires chronic concomitant treatment of strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort).

• Uncontrolled, significant intercurrent illness including, but not limited to, cardiovascular disorders, gastrointestinal disorders, active infections, non-healing wounds, recent surgery.

• Clinically significant hematemesis or hemoptysis, or other signs indicative of pulmonary hemorrhage in the last 3 months, or history of other significant bleeding in the past 6 months.

• Cavitating pulmonary lesion(s) or a lesion invading or encasing a major blood vessel.

• QTcF > 500 ms within 7 days of randomization.

• Unable to swallow capsules or tablets.

• Previously-identified allergy or hypersensitivity to components of the study treatment formulations.

• Another diagnosis of malignancy requiring systemic treatment within 2 years of randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35205
2		Anchorage	Alaska	United States	99508
3		Phoenix	Arizona	United States	85016
4		Scottsdale	Arizona	United States	85255
5		Tucson	Arizona	United States	85710
6		Jonesboro	Arkansas	United States	72401
7		Duarte	California	United States	91010
8		Highland	California	United States	92346
9		La Jolla	California	United States	92093
10		Los Angeles	California	United States	90033
11		Montebello	California	United States	90640
12		Orange	California	United States	92868
13		Palo Alto	California	United States	94301
14		Rancho Mirage	California	United States	92270
15		Saint Helena	California	United States	94574
16		San Marcos	California	United States	92069
17		Vallejo	California	United States	94589
18		Aurora	Colorado	United States	80045
19		New Haven	Connecticut	United States	06520
20		Southington	Connecticut	United States	06489
21		Miami Beach	Florida	United States	33140
22		Ocala	Florida	United States	34471
23		Orlando	Florida	United States	32806
24		Tampa	Florida	United States	33612
25		Titusville	Florida	United States	32796
26		Wellington	Florida	United States	33449
27		West Palm Beach	Florida	United States	33401
28		Athens	Georgia	United States	30607
29		Atlanta	Georgia	United States	30318
30		Marietta	Georgia	United States	30060
31		Galesburg	Illinois	United States	61401
32		Niles	Illinois	United States	60714
33		Ames	Iowa	United States	50010
34		Sioux City	Iowa	United States	51101
35		Wichita	Kansas	United States	67214
36		Hazard	Kentucky	United States	41701
37		Louisville	Kentucky	United States	40202
38		Brewer	Maine	United States	04412
39		Baltimore	Maryland	United States	21201
40		Bethesda	Maryland	United States	20817
41		Towson	Maryland	United States	21204
42		Boston	Massachusetts	United States	02114
43		Boston	Massachusetts	United States	02118
44		Methuen	Massachusetts	United States	01844
45		Detroit	Michigan	United States	48202
46		Wyoming	Michigan	United States	49509
47		Minneapolis	Minnesota	United States	55455
48		Jefferson City	Missouri	United States	65109
49		Springfield	Missouri	United States	65804
50		Lincoln	Nebraska	United States	68506
51		Omaha	Nebraska	United States	68130
52		Hackensack	New Jersey	United States	07601
53		Lawrenceville	New Jersey	United States	08648
54		Albany	New York	United States	12208
55		Garden City	New York	United States	11530
56		New York	New York	United States	10065
57		Pinehurst	North Carolina	United States	28374
58		Bismarck	North Dakota	United States	58501
59		Cincinnati	Ohio	United States	45219
60		Columbus	Ohio	United States	43221
61		Portland	Oregon	United States	97227
62		Bryn Mawr	Pennsylvania	United States	19010
63		Hershey	Pennsylvania	United States	17033
64		Lancaster	Pennsylvania	United States	17604
65		Greenville	South Carolina	United States	29615
66		Chattanooga	Tennessee	United States	37421
67		Amarillo	Texas	United States	79106
68		Bedford	Texas	United States	76022
69		Houston	Texas	United States	77024
70		Laredo	Texas	United States	78041
71		San Antonio	Texas	United States	78217
72		Salt Lake City	Utah	United States	84112
73		Burlington	Vermont	United States	05405
74		Fairfax	Virginia	United States	22031
75		Newport News	Virginia	United States	23601
76		Spokane	Washington	United States	99204
77		Green Bay	Wisconsin	United States	54311
78		Albury	New South Wales	Australia	2640
79		Concord	New South Wales	Australia	2193
80		Darlinghurst	New South Wales	Australia	2010
81		Kogarah	New South Wales	Australia	2217
82		Port Macquarie	New South Wales	Australia	2444
83		Randwick	New South Wales	Australia	2031
84		Wahroonga	New South Wales	Australia	2076
85		Westmead	New South Wales	Australia	2145
86		South Brisbane	Queensland	Australia	4101
87		Southport	Queensland	Australia	4215
88		Woolloongabba	Queensland	Australia	4102
89		Adelaide	South Australia	Australia	5000
90		Kurralta Park	South Australia	Australia	5037
91		Hobart	Tasmania	Australia	7000
92		Bentleigh East	Victoria	Australia	3165
93		Box Hill	Victoria	Australia	3128
94		Wodonga	Victoria	Australia	3690
95		Perth	Western Australia	Australia	6000
96		Linz		Austria	4010
97		Salzburg		Austria	5020
98		Wein		Austria	1100
99		Wien		Austria	1090
100		Aalst		Belgium	9300
101		Bonheiden		Belgium	2820
102		Brussels		Belgium	1000
103		Brussels		Belgium	1090
104		Brussels		Belgium	1200
105		Gent		Belgium	9000
106		Hasselt		Belgium	3500
107		Leuven		Belgium	B-3000
108		Liège		Belgium	4000
109		Roeselare		Belgium	8800
110		Calgary	Alberta	Canada	T2N 4N2
111		Vancouver	British Columbia	Canada	V5Z 4E6
112		Miramichi	New Brunswick	Canada	E1V 1Y3
113		Halifax	Nova Scotia	Canada	B3H 1V7
114		London	Ontario	Canada	N6A 4L6
115		Owen Sound	Ontario	Canada	N4K 2J1
116		Montreal	Quebec	Canada	H2L4M1
117		Quebec		Canada	G1R 2J6
118		Angers		France	49933
119		Besançon		France	25030
120		Bordeaux		France	33076
121		Caen		France	14076
122		Clermont Ferrand		France	63011
123		Dijon		France	21079
124		La Roche sur Yon		France	85925
125		Le Mans		France	72000
126		Lille		France	59000
127		Lyon Cedex 08		France	69373
128		Marseille		France	13273
129		Nancy		France	54100
130		Paris		France	75005
131		Paris		France	75010
132		Paris		France	75014
133		Paris		France	75015
134		Paris		France	75230
135		Pierre Benite		France	69495
136		Rennes		France	35042
137		Saint Herblain		France	44805
138		Strasbourg		France	67000
139		Suresnes		France	92151
140		Villejuif Cedex		France	94805
141		Aachen		Germany	52062
142		Aachen		Germany	52074
143		Berlin		Germany	12200
144		Berlin		Germany	13055
145		Braunschweig		Germany	38126
146		Dresden		Germany	01307
147		Dusseldorf		Germany	40225
148		Frankfurt am Main		Germany	60488
149		Freiburg		Germany	79106
150		Furth		Germany	90766
151		Gütersloh		Germany	33332
152		Hamburg		Germany	20246
153		Hamburg		Germany	22399
154		Hamburg		Germany	22763
155		Hannover		Germany	30625
156		Heidelberg		Germany	69120
157		Homburg		Germany	66421
158		Kassel		Germany	34125
159		Kempen		Germany	47906
160		Kirchheim		Germany	73230
161		Koln		Germany	50968
162		Mannheim		Germany	68167
163		Munchen		Germany	81675
164		Munster		Germany	48149
165		Nurtingen		Germany	72622
166		Offenburg		Germany	77654
167		Traunstein		Germany	83278
168		Tubingen		Germany	72076
169		Weiden		Germany	92637
170		Wuppertal		Germany	42103
171		Cork		Ireland
172		Dublin		Ireland	24
173		Dublin		Ireland	7
174		Galway		Ireland
175		Ancona		Italy	60126
176		Arezzo		Italy	52100
177		Aviano		Italy	33081
178		Brindisi		Italy	72100
179		Cremona		Italy	26100
180		Genova		Italy	16132
181		Livorno		Italy	57123
182		Meldola		Italy	47014
183		Milano		Italy	20132
184		Milano		Italy	20133
185		Milano		Italy	20162
186		Modena		Italy	41124
187		Napoli		Italy	80131
188		Novara		Italy	28100
189		Orbassano		Italy	10043
190		Padova		Italy	35128
191		Pavia		Italy	27100
192		Pisa		Italy	56126
193		Pordenone		Italy	33170
194		Ravenna		Italy	48121
195		Rimini		Italy	47900
196		Roma		Italy	00128
197		Roma		Italy	00152
198		Rozzano		Italy	20089
199		Terni		Italy	05100
200		Torino		Italy	10126
201		Verona		Italy	37134
202		Amsterdam		Netherlands	1066 CX
203		Groningen		Netherlands	9713 GZ
204		Groningen		Netherlands	9728 NT
205		Hoofddorp		Netherlands	2134 TM
206		Nieuwegein		Netherlands	3435 CM
207		Nijmegen		Netherlands	6525 GA
208		Rotterdam		Netherlands	3045 PM
209		Rotterdam		Netherlands	3075 EA
210		Tilburg		Netherlands	5042 AD
211		Zwolle		Netherlands	8025 AB
212		Ponce		Puerto Rico	00716
213		Málaga	Andalucía	Spain	29010
214		Sevilla	Andalucía	Spain	41013
215		Oviedo	Asturias	Spain	33006
216		Palma de Mallorca	Baleares	Spain	07010
217		La Laguna	Canarias	Spain	38320
218		Badalona	Cataluña	Spain	08916
219		Barcelona	Cataluña	Spain	08003
220		Barcelona	Cataluña	Spain	08023
221		Barcelona	Cataluña	Spain	08025
222		Barcelona	Cataluña	Spain	08035
223		Barcelona	Cataluña	Spain	08036
224		L'Hospitalet de Llobregat	Cataluña	Spain	08908
225		Manresa	Cataluña	Spain	08243
226		Elche	Comunidad Valenciana	Spain	03016
227		Valencia	Comunidad Valenciana	Spain	46009
228		A Coruña	Galicia	Spain	15006
229		Santiago de Compostela	Galicia	Spain	15706
230		Madrid	Madrid, Communidad De	Spain	28007
231		Madrid	Madrid, Communidad De	Spain	28040
232		Madrid	Madrid, Communidad De	Spain	28041
233		Madrid	Madrid, Communidad De	Spain	28050
234		Madrid	Madrid, Communidad De	Spain	28922
235		Majadahonda	Madrid, Communidad De	Spain	28222
236		Pamplona	Navarra	Spain	31008
237		Gotenborg		Sweden	SE 41345
238		Malmo		Sweden	SE-20502
239		Orebro		Sweden	SE-70185
240		Stockholm		Sweden	SE-17176
241		Umea		Sweden	SE-90184
242		Uppsala		Sweden	SE 75185
243		Vaxjo		Sweden	SE-35185
244		Aberdeen		United Kingdom	AB25 2ZN
245		Bath		United Kingdom	BA1 3NG
246		Birmingham		United Kingdom	B15 2TH
247		Brighton		United Kingdom	BN2 5BE
248		Bristol		United Kingdom	BS2 8ED
249		Cambridge		United Kingdom	CB2 2QQ
250		Cardiff		United Kingdom	CF14 2TL
251		Cottingham		United Kingdom	HU16 5JQ
252		Edinburgh		United Kingdom	EH4 2XU
253		Inverness		United Kingdom	IV2 3UJ
254		Lancaster		United Kingdom	LA1 4RP
255		Leeds		United Kingdom	LS9 7TF
256		London		United Kingdom	SE1 9RT
257		London		United Kingdom	W12 0HS
258		Maidstone		United Kingdom	ME16 9QQ
259		Northwood		United Kingdom	HA6 2RN
260		Plymouth		United Kingdom	PL6 8DH
261		Sheffield		United Kingdom	S10 2SJ
262		Southampton		United Kingdom	S16 6YD
263		Sutton		United Kingdom	SM2 5PT
264		Wirral		United Kingdom	CH63 4JY

Sponsors and Collaborators

• Exelixis

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Exelixis
• ClinicalTrials.gov Identifier: NCT01605227
• Other Study ID Numbers: XL184-307; 2012-001834-33
• First Posted: May 24, 2012
• Last Update Posted: Mar 14, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Exelixis: prostate cancer; castration resistant prostate cancer; bone pain; CRPC
• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone

Study Results

Participant Flow

Recruitment Details	First patient enrolled: 02 July 2012 (first subject randomized), Data cut off date: 07 July 2014

Arm/Group Title	Cabozantinib	Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules. Cabozantinib (XL184) 60 mg tablets orally once daily plus prednisone-matched placebo orally twice daily.	Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib. Prednisone 5 mg capsules orally twice daily plus cabozantinib-matched placebo orally once daily.
Period Title: Overall Study
STARTED	682	346
COMPLETED	61	17
NOT COMPLETED	621	329

Baseline Characteristics

Arm/Group Title	Cabozantinib	Prednisone	Total
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules. Cabozantinib (XL184) 60 mg tablets orally once daily plus prednisone-matched placebo orally twice daily.	Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib. Prednisone 5 mg capsules orally twice daily plus cabozantinib-matched placebo orally once daily.	Total of all reporting groups
Overall Participants	682	346	1028
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	165 24.2%	97 28%	262 25.5%
>=65 years	517 75.8%	249 72%	766 74.5%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	682 100%	346 100%	1028 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.3%	1 0.1%
Asian	2 0.3%	0 0%	2 0.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	14 2.1%	6 1.7%	20 1.9%
White	520 76.2%	265 76.6%	785 76.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	146 21.4%	74 21.4%	220 21.4%
Region of Enrollment (Count of Participants)
North America	119 17.4%	63 18.2%	182 17.7%
Europe	528 77.4%	256 74%	784 76.3%
Australia	35 5.1%	27 7.8%	62 6%
Prior cabazitaxel (per CRF) (Count of Participants)
Yes	261 38.3%	132 38.2%	393 38.2%
No	421 61.7%	214 61.8%	635 61.8%
Brief Pain Inventory (BPI) Item 3 (per CRF) (Count of Participants)
<4	389 57%	196 56.6%	585 56.9%
≥4	284 41.6%	148 42.8%	432 42%
Missing	9 1.3%	2 0.6%	11 1.1%
ECOG Performance Status (per CRF) (participants) [Number]
0/1 (asymptomatic or symptomatic but ambulatory)	605 88.7%	303 87.6%	908 88.3%
2 (ambulatory but can't carry out work activities)	76 11.1%	43 12.4%	119 11.6%
Missing	1 0.1%	0 0%	1 0.1%
Opioid narcotic use within 24 hours (per solicited oploid CRF) (Count of Participants)
Count of Participants [Participants]	454 66.6%	228 65.9%	682 66.3%
Concomitant prednisone/prednisolone at randomization (Count of Participants)
Count of Participants [Participants]	289 42.4%	142 41%	431 41.9%
Time from diagnosis to study entry (years) [Median (Full Range) ]
Median (Full Range) [years]	6.68	6.98	6.83
Bone scan lesion area (mm^2) [Median (Full Range) ]
Median (Full Range) [mm^2]	45,635.5	41,746.0	44,782.0
Extent of metastasis (participants) [Number]
None	0 0%	0 0%	0 0%
Bone	681 99.9%	346 100%	1027 99.9%
Lymph node	313 45.9%	140 40.5%	453 44.1%
Visceral	133 19.5%	58 16.8%	191 18.6%
Liver	91 13.3%	35 10.1%	126 12.3%
Lung	69 10.1%	29 8.4%	98 9.5%
Other soft tissue	39 5.7%	23 6.6%	62 6%
No. of prior anticancer agents (participants) [Number]
2	57 8.4%	31 9%	88 8.6%
≥3	625 91.6%	315 91%	940 91.4%
Baseline LDH (U/L) [Median (Full Range) ]
Median (Full Range) [U/L]	230	230	230
Baseline PSA (μg/L) [Median (Full Range) ]
Median (Full Range) [μg/L]	192	195	192
Baseline serum testosterone (<50 ng/dL) (Count of Participants)
Count of Participants [Participants]	677 99.3%	345 99.7%	1022 99.4%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	The primary analysis of OS is defined as the time from randomization to death due to any cause. Participants that had not died or were permanently lost to follow-up were censored at the last known date alive. Median OS was calculated using Kaplan-Meier estimates. Analysis for OS was performed after 614 events had occurred.
Time Frame	OS was measured from the time of randomization until 614 events, approximately 24 months after study start

Outcome Measure Data

Analysis Population Description

The Intent to Treat (ITT) population was used and included 1028 randomized subjects (682 cabozantinib, 346 prednisone).

Arm/Group Title	Cabozantinib	Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules. Cabozantinib (XL184) 60 mg tablets orally once daily plus prednisone-matched placebo orally twice daily.	Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib. Prednisone 5 mg capsules orally twice daily plus cabozantinib-matched placebo orally once daily.
Measure Participants	682	346
Median (95% Confidence Interval) [months]	11.0	9.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib, Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.213
	Comments
	Method	Log Rank
	Comments	The Log-Rank test was stratified by prior cabazitaxel, baseline pain severity and baseline ECOG performance status.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Bone Scan Response (BSR)
Description	BSR is defined as >=30% reduction in the bone scan lesion area (BSLA) compared with baseline. Confirmation of bone scan was not required for response or progression. Bone scans were evaluated by an independent radiology facility (IRF) for response.
Time Frame	BSR was measured at the end of Week 12 as determined by the IRF

Outcome Measure Data

Analysis Population Description

Analysis was conducted on the ITT population (682 cabozantinib, 346 prednisone) for Bone Scan Response (BSR) at Week 12.

Arm/Group Title	Cabozantinib	Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules. Cabozantinib (XL184) 60 mg tablets orally once daily plus prednisone-matched placebo orally twice daily.	Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib. Prednisone 5 mg capsules orally twice daily plus cabozantinib-matched placebo orally once daily.
Measure Participants	682	346
Number (95% Confidence Interval) [percentage of participants]	42 6.2%	3 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib, Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The Cochran-Mantel-Haenszel (CMH) Test was stratified by prior cabazitaxel, baseline pain severity and baseline ECOG performance status.

3. Other Pre-specified Outcome

Title	Progression-free Survival (PFS)
Description	The exploratory analysis of PFS is the time from randomization to date of first documented radiographic progression (bone and/or soft tissue) according to the investigator's assessment or death. PFS was defined per mRECIST 1.1 and included evaluation of measurable, nonmeasurable, target and nontarget lesions. A Kaplan-Meier analysis was performed to estimate the median duration.
Time Frame	Duration of PFS was defined as time from the date of randomization to earlier of date of radiographic progression (bone/andor soft tissue) according to the investigator's assessment or death, assessed for up to approximately 24 months

Outcome Measure Data

Analysis Population Description

The Intent to Treat (ITT) population was used and include 1028 randomized subjects (682 cabozantinib, 346 prednisone) with a data cut off date of 07 July 2014.

Arm/Group Title	Cabozantinib	Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules. Cabozantinib (XL184) 60 mg tablets orally once daily plus prednisone-matched placebo orally twice daily.	Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib. Prednisone 5 mg capsules orally twice daily plus cabozantinib-matched placebo orally once daily.
Measure Participants	682	346
Median (95% Confidence Interval) [months]	5.6	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib, Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments	The Log-Rank Test was stratified by prior cabazitaxel, baseline pain severity, and baseline Eastern Cooperative Oncology Group Performance Status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 92 weeks
Adverse Event Reporting Description	Safety was assessed based on the date of first dose and at minimum every 3 weeks up to Week 12 and every 6 weeks thereafter. The safety data includes subjects who were randomized and treated. Of 1028 patients, 682 were randomized to receive cabozantinib and 346 prednisone. The Safety population comprised of 1023 patients (681 cabozantinib, 342 prednisone).
Arm/Group Title	Cabozantinib		Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules. Cabozantinib (XL184) 60 mg tablets orally once daily plus prednisone-matched placebo orally twice daily.		Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib. Prednisone 5 mg capsules orally twice daily plus cabozantinib-matched placebo orally once daily.
All Cause Mortality
	Cabozantinib		Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cabozantinib		Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	420/681 (61.7%)		181/342 (52.9%)
Blood and lymphatic system disorders
Anaemia	32/681 (4.7%)		16/342 (4.7%)
Anaemia of malignant disease	1/681 (0.1%)		1/342 (0.3%)
Disseminated intravascular coagulation	1/681 (0.1%)		0/342 (0%)
Febrile neutropenia	3/681 (0.4%)		1/342 (0.3%)
Lymphadenopathy	1/681 (0.1%)		0/342 (0%)
Neutropenia	1/681 (0.1%)		1/342 (0.3%)
Pancytopenia	2/681 (0.3%)		2/342 (0.6%)
Thrombocytopenia	6/681 (0.9%)		4/342 (1.2%)
Cardiac disorders
Acute coronary syndrome	1/681 (0.1%)		1/342 (0.3%)
Acute myocardial infarction	5/681 (0.7%)		0/342 (0%)
Angina pectoris	2/681 (0.3%)		0/342 (0%)
Arrhythmia	1/681 (0.1%)		0/342 (0%)
Atrial fibrillation	5/681 (0.7%)		2/342 (0.6%)
Atrioventricular block complete	1/681 (0.1%)		0/342 (0%)
Cardiac arrest	0/681 (0%)		1/342 (0.3%)
Cardiac failure	4/681 (0.6%)		1/342 (0.3%)
Cardiac failure congestive	2/681 (0.3%)		0/342 (0%)
Coronary artery stenosis	0/681 (0%)		1/342 (0.3%)
Myocardial infarction	1/681 (0.1%)		1/342 (0.3%)
Myocardial ischaemia	1/681 (0.1%)		0/342 (0%)
Stress cardiomyopathy	0/681 (0%)		1/342 (0.3%)
Congenital, familial and genetic disorders
Cystic lymphangioma	1/681 (0.1%)		0/342 (0%)
Metabolic myopathy	1/681 (0.1%)		0/342 (0%)
Ear and labyrinth disorders
Vertigo	1/681 (0.1%)		1/342 (0.3%)
Endocrine disorders
Adrenal insufficiency	1/681 (0.1%)		0/342 (0%)
Cushing's syndrome	1/681 (0.1%)		0/342 (0%)
Hypoaldosteronism	1/681 (0.1%)		0/342 (0%)
Eye disorders
Diplopia	1/681 (0.1%)		1/342 (0.3%)
Visual acuity reduced	1/681 (0.1%)		0/342 (0%)
Uveitis	1/681 (0.1%)		0/342 (0%)
Gastrointestinal disorders
Abdominal distension	1/681 (0.1%)		0/342 (0%)
Abdominal pain	8/681 (1.2%)		3/342 (0.9%)
Abdominal pain lower	1/681 (0.1%)		0/342 (0%)
Abdominal pain upper	2/681 (0.3%)		0/342 (0%)
Anal fissure	1/681 (0.1%)		0/342 (0%)
Anal fistula	2/681 (0.3%)		0/342 (0%)
Anal inflammation	1/681 (0.1%)		0/342 (0%)
Aphthous stomatitis	0/681 (0%)		1/342 (0.3%)
Ascites	1/681 (0.1%)		1/342 (0.3%)
Colitis ischaemic	1/681 (0.1%)		0/342 (0%)
Constipation	12/681 (1.8%)		6/342 (1.8%)
Diarrhoea	10/681 (1.5%)		2/342 (0.6%)
Diverticular perforation	1/681 (0.1%)		0/342 (0%)
Duodenal ulcer	1/681 (0.1%)		0/342 (0%)
Dysphagia	1/681 (0.1%)		0/342 (0%)
Enterovesical fistula	1/681 (0.1%)		0/342 (0%)
Erosive oesophagitis	1/681 (0.1%)		0/342 (0%)
Faecaloma	2/681 (0.3%)		0/342 (0%)
Gastric antral vascular estasia	1/681 (0.1%)		0/342 (0%)
Gastritis	0/681 (0%)		1/342 (0.3%)
Gastrointestinal haemorrhage	3/681 (0.4%)		1/342 (0.3%)
Gastrointestinal obstruction	2/681 (0.3%)		0/342 (0%)
Gastrointestinal perforation	1/681 (0.1%)		0/342 (0%)
Haematemesis	1/681 (0.1%)		0/342 (0%)
Haemorrhoidal haemorrhage	2/681 (0.3%)		0/342 (0%)
Inguinal hernia, obstructive	1/681 (0.1%)		0/342 (0%)
Intestinal ischaemia	1/681 (0.1%)		0/342 (0%)
Intestinal obstruction	2/681 (0.3%)		1/342 (0.3%)
Intestinal perforation	1/681 (0.1%)		0/342 (0%)
Intra-abdominal haemorrhage	0/681 (0%)		1/342 (0.3%)
Large intestine perforation	3/681 (0.4%)		0/342 (0%)
Mallory-Weiss syndrome	1/681 (0.1%)		0/342 (0%)
Mouth ulceration	1/681 (0.1%)		0/342 (0%)
Nausea	23/681 (3.4%)		6/342 (1.8%)
Obstruction gastric	1/681 (0.1%)		0/342 (0%)
Oesophagitis	1/681 (0.1%)		0/342 (0%)
Pancreatitis	1/681 (0.1%)		0/342 (0%)
Rectal haemorrhage	0/681 (0%)		1/342 (0.3%)
Small intestinal obstrucion	1/681 (0.1%)		0/342 (0%)
Small intestinal perforation	2/681 (0.3%)		0/342 (0%)
Stomatitis	1/681 (0.1%)		0/342 (0%)
Subileus	0/681 (0%)		1/342 (0.3%)
Vomiting	28/681 (4.1%)		6/342 (1.8%)
General disorders
Asthenia	18/681 (2.6%)		3/342 (0.9%)
Chest pain	2/681 (0.3%)		0/342 (0%)
Death	4/681 (0.6%)		1/342 (0.3%)
Device dislocation	1/681 (0.1%)		0/342 (0%)
Device occlusion	1/681 (0.1%)		0/342 (0%)
Drug withdrawal syndrome	1/681 (0.1%)		0/342 (0%)
Euthanasia	3/681 (0.4%)		0/342 (0%)
Fatigue	20/681 (2.9%)		3/342 (0.9%)
General physical health deterioration	52/681 (7.6%)		22/342 (6.4%)
Influenza like illness	1/681 (0.1%)		0/342 (0%)
Local swelling	2/681 (0.3%)		1/342 (0.3%)
Malaise	5/681 (0.7%)		0/342 (0%)
Mucosal inflammation	8/681 (1.2%)		0/342 (0%)
Multi-organ failure	2/681 (0.3%)		2/342 (0.6%)
Non-cardiac chest pain	2/681 (0.3%)		1/342 (0.3%)
Oedema peripheral	3/681 (0.4%)		1/342 (0.3%)
Pain	10/681 (1.5%)		7/342 (2%)
Performance status decreased	1/681 (0.1%)		0/342 (0%)
Pyrexia	15/681 (2.2%)		6/342 (1.8%)
Sudden death	1/681 (0.1%)		1/342 (0.3%)
Hepatobiliary disorders
Bile duct obstruction	1/681 (0.1%)		0/342 (0%)
Bile duct stenosis	0/681 (0%)		1/342 (0.3%)
Cholecystitis	2/681 (0.3%)		0/342 (0%)
Hepatic failure	3/681 (0.4%)		0/342 (0%)
Hepatitis	1/681 (0.1%)		0/342 (0%)
Hydrocholecystis	1/681 (0.1%)		0/342 (0%)
Hyperbilirubinaemia	1/681 (0.1%)		1/342 (0.3%)
Jaundice	1/681 (0.1%)		0/342 (0%)
Infections and infestations
Abdominal sepsis	1/681 (0.1%)		0/342 (0%)
Abscess	1/681 (0.1%)		0/342 (0%)
Anal abscess	4/681 (0.6%)		0/342 (0%)
Appendicitis	1/681 (0.1%)		0/342 (0%)
Arthritis infective	1/681 (0.1%)		0/342 (0%)
Aspergillus infection	1/681 (0.1%)		0/342 (0%)
Bronchitis	0/681 (0%)		1/342 (0.3%)
Cellulitis	1/681 (0.1%)		0/342 (0%)
Clostridium difficile colitis	1/681 (0.1%)		0/342 (0%)
Colonic abscess	3/681 (0.4%)		0/342 (0%)
Cystitis	1/681 (0.1%)		0/342 (0%)
Device related infection	1/681 (0.1%)		2/342 (0.6%)
Device related sepsis	2/681 (0.3%)		1/342 (0.3%)
Endocarditis	1/681 (0.1%)		0/342 (0%)
Endocarditis staphylococcal	1/681 (0.1%)		0/342 (0%)
Enterobacter infection	1/681 (0.1%)		0/342 (0%)
Enterobactar sepsis	0/681 (0%)		1/342 (0.3%)
Enterococcal sepsis	1/681 (0.1%)		0/342 (0%)
Erysipelas	1/681 (0.1%)		0/342 (0%)
Escherichia urinary tract infection	0/681 (0%)		1/342 (0.3%)
Gastroenteritis	3/681 (0.4%)		1/342 (0.3%)
Gastroenteritis viral	0/681 (0%)		1/342 (0.3%)
Gastrointestinal infection	1/681 (0.1%)		0/342 (0%)
Herpes simplex	1/681 (0.1%)		0/342 (0%)
Herpes zoster	1/681 (0.1%)		0/342 (0%)
Localised infection	1/681 (0.1%)		0/342 (0%)
Lower respiratory tract infection	2/681 (0.3%)		1/342 (0.3%)
Lung infection	5/681 (0.7%)		0/342 (0%)
Neutropenic sepsis	1/681 (0.1%)		0/342 (0%)
Oral candidiasis	1/681 (0.1%)		0/342 (0%)
Osteomyelilitis	1/681 (0.1%)		0/342 (0%)
Otitis externa	1/681 (0.1%)		0/342 (0%)
Periorbital cellulitis	1/681 (0.1%)		0/342 (0%)
Pharyngeal abscess	1/681 (0.1%)		0/342 (0%)
Pilonidal cyst	1/681 (0.1%)		0/342 (0%)
Pneumonia	17/681 (2.5%)		12/342 (3.5%)
Pneumonia klebsiella	1/681 (0.1%)		0/342 (0%)
Post procedural infection	1/681 (0.1%)		0/342 (0%)
Pulmonary sepsis	2/681 (0.3%)		0/342 (0%)
Pulpitis dental	0/681 (0%)		1/342 (0.3%)
Pyelonephritis	1/681 (0.1%)		1/342 (0.3%)
Pyelonephritis acute	1/681 (0.1%)		0/342 (0%)
Respiratory tract infection	3/681 (0.4%)		0/342 (0%)
Sepsis	11/681 (1.6%)		5/342 (1.5%)
Septic shock	3/681 (0.4%)		2/342 (0.6%)
Sinusitis	1/681 (0.1%)		0/342 (0%)
Spinal cord infection	1/681 (0.1%)		5/342 (1.5%)
Staphylococcal infection	0/681 (0%)		1/342 (0.3%)
Staphylococcal sepsis	2/681 (0.3%)		1/342 (0.3%)
Streptococcal bacteraemia	1/681 (0.1%)		1/342 (0.3%)
Streptococcal infection	1/681 (0.1%)		0/342 (0%)
Subcutaneous abscess	1/681 (0.1%)		0/342 (0%)
Tonsillitis	1/681 (0.1%)		0/342 (0%)
Tooth abscess	1/681 (0.1%)		0/342 (0%)
Tracheobronchitis	1/681 (0.1%)		0/342 (0%)
Upper respiratory tract infection	0/681 (0%)		1/342 (0.3%)
Urinary tract infection	13/681 (1.9%)		6/342 (1.8%)
Urinary tract infection enterococcal	0/681 (0%)		1/342 (0.3%)
Urinary tract infection staphylococcal	1/681 (0.1%)		0/342 (0%)
Urosepsis	7/681 (1%)		1/342 (0.3%)
Viral infection	0/681 (0%)		1/342 (0.3%)
Viral pharyngitis	1/681 (0.1%)		0/342 (0%)
Wound infection	1/681 (0.1%)		0/342 (0%)
Infection	2/681 (0.3%)		2/342 (0.6%)
Injury, poisoning and procedural complications
Accidental overdose	0/681 (0%)		1/342 (0.3%)
Chest injury	1/681 (0.1%)		0/342 (0%)
Craniocerebral injury	0/681 (0%)		1/342 (0.3%)
Fall	3/681 (0.4%)		0/342 (0%)
Head injury	1/681 (0.1%)		0/342 (0%)
Keratorhexis	1/681 (0.1%)		0/342 (0%)
Postoperative wound complication	1/681 (0.1%)		0/342 (0%)
Sternal fracture	1/681 (0.1%)		0/342 (0%)
Subdural haematoma	2/681 (0.3%)		1/342 (0.3%)
Toxicity to various agents	1/681 (0.1%)		1/342 (0.3%)
Traumatic fracture	1/681 (0.1%)		0/342 (0%)
Upper limb fracture	0/681 (0%)		1/342 (0.3%)
Urostomy complication	1/681 (0.1%)		0/342 (0%)
Wound complication	0/681 (0%)		1/342 (0.3%)
Wound dehiscence	1/681 (0.1%)		0/342 (0%)
Investigations
Alanine aminotransferase increased	2/681 (0.3%)		0/342 (0%)
Aspartate aminotransferase increased	2/681 (0.3%)		0/342 (0%)
Blood alkaline phosphatase increased	2/681 (0.3%)		0/342 (0%)
Blood bilirubin increased	1/681 (0.1%)		0/342 (0%)
Blood creatine phosphokinase increased	0/681 (0%)		1/342 (0.3%)
Blood creatine increased	2/681 (0.3%)		0/342 (0%)
Clostridium test positive	1/681 (0.1%)		0/342 (0%)
Gamma-glutamyltransferase increased	1/681 (0.1%)		0/342 (0%)
Liver function test abnormal	1/681 (0.1%)		2/342 (0.6%)
Platelet count decreased	1/681 (0.1%)		0/342 (0%)
Red blood cell count decreased	0/681 (0%)		1/342 (0.3%)
Troponin T increased	0/681 (0%)		1/342 (0.3%)
Metabolism and nutrition disorders
Cachexia	0/681 (0%)		1/342 (0.3%)
Decreased appetite	15/681 (2.2%)		2/342 (0.6%)
Dehydration	20/681 (2.9%)		1/342 (0.3%)
Diabetes mellitus	1/681 (0.1%)		2/342 (0.6%)
Diabetes mellitus inadequate control	0/681 (0%)		1/342 (0.3%)
Failure to thrive	2/681 (0.3%)		1/342 (0.3%)
Hyperglyceaemia	0/681 (0%)		1/342 (0.3%)
Hyperkalaemia	1/681 (0.1%)		1/342 (0.3%)
Hypocalcaemia	3/681 (0.4%)		0/342 (0%)
Hypokalaemia	5/681 (0.7%)		1/342 (0.3%)
Hypomagnesaemia	1/681 (0.1%)		0/342 (0%)
Hyponatraemia	7/681 (1%)		1/342 (0.3%)
Hypophosphataemia	3/681 (0.4%)		0/342 (0%)
Malnutrition	1/681 (0.1%)		0/342 (0%)
Tumour lysis syndrome	1/681 (0.1%)		0/342 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/681 (0.9%)		4/342 (1.2%)
Back pain	14/681 (2.1%)		8/342 (2.3%)
Bone pain	15/681 (2.2%)		11/342 (3.2%)
Flank pain	0/681 (0%)		1/342 (0.3%)
Muscular weakness	4/681 (0.6%)		2/342 (0.6%)
Musculoskeletal chest pain	2/681 (0.3%)		0/342 (0%)
Musculoskeletal pain	3/681 (0.4%)		2/342 (0.6%)
Myalgia	1/681 (0.1%)		2/342 (0.6%)
Myositis	1/681 (0.1%)		0/342 (0%)
Neck pain	3/681 (0.4%)		1/342 (0.3%)
Osteonecrosis of jaw	4/681 (0.6%)		0/342 (0%)
Pain in extremity	5/681 (0.7%)		1/342 (0.3%)
Pathological fracture	4/681 (0.6%)		4/342 (1.2%)
Rhabdomyolysis	2/681 (0.3%)		0/342 (0%)
Spinal column stenosis	0/681 (0%)		1/342 (0.3%)
Spinal pain	1/681 (0.1%)		0/342 (0%)
Spondylolisthesis	1/681 (0.1%)		0/342 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/681 (0.1%)		0/342 (0%)
Cancer pain	1/681 (0.1%)		2/342 (0.6%)
Hormone-refractory prostate cancer	1/681 (0.1%)		0/342 (0%)
Lymphangiosis carcinomatosa	1/681 (0.1%)		0/342 (0%)
Malignant melanoma	0/681 (0%)		1/342 (0.3%)
Malignant neoplasm progression	1/681 (0.1%)		1/342 (0.3%)
Meningioma	0/681 (0%)		1/342 (0.3%)
Metastases to central nervous system	5/681 (0.7%)		3/342 (0.9%)
Metastases to lymph nodes	1/681 (0.1%)		0/342 (0%)
Metastases to meninges	2/681 (0.3%)		0/342 (0%)
Metastases to spine	0/681 (0%)		2/342 (0.6%)
Metastatic pain	19/681 (2.8%)		12/342 (3.5%)
Myelodysplastic syndrome	0/681 (0%)		1/342 (0.3%)
Neoplasm progression	1/681 (0.1%)		0/342 (0%)
Nodular melanoma	1/681 (0.1%)		0/342 (0%)
Pancreatic carcinoma	1/681 (0.1%)		0/342 (0%)
Prostate cancer	52/681 (7.6%)		27/342 (7.9%)
Prostate cancer metastatic	0/681 (0%)		1/342 (0.3%)
Second primary malignancy	1/681 (0.1%)		0/342 (0%)
Tumour haemorrhage	1/681 (0.1%)		0/342 (0%)
Tumour pain	1/681 (0.1%)		0/342 (0%)
Nervous system disorders
Cauda equina syndrome	1/681 (0.1%)		1/342 (0.3%)
Cerebellar infarction	1/681 (0.1%)		0/342 (0%)
Cerebral haematoma	2/681 (0.3%)		0/342 (0%)
Cerebral haemorrhage	3/681 (0.4%)		0/342 (0%)
Cerebral infarction	1/681 (0.1%)		0/342 (0%)
Cerebral ischaemia	2/681 (0.3%)		1/342 (0.3%)
Cerebrovascular accident	4/681 (0.6%)		3/342 (0.9%)
Cognitive disorder	1/681 (0.1%)		0/342 (0%)
Convulsion	1/681 (0.1%)		1/342 (0.3%)
Dizziness	2/681 (0.3%)		0/342 (0%)
Dyskinesia	1/681 (0.1%)		0/342 (0%)
Facial paresis	1/681 (0.1%)		0/342 (0%)
Haemorrhage intracranial	1/681 (0.1%)		0/342 (0%)
Headache	2/681 (0.3%)		3/342 (0.9%)
Hemiparesis	0/681 (0%)		1/342 (0.3%)
Hypoaesthesia	1/681 (0.1%)		4/342 (1.2%)
Ischaemic stroke	1/681 (0.1%)		1/342 (0.3%)
Lethargy	2/681 (0.3%)		0/342 (0%)
Leukoencephalopathy	1/681 (0.1%)		0/342 (0%)
Loss of consciousness	3/681 (0.4%)		1/342 (0.3%)
Memory impairment	0/681 (0%)		1/342 (0.3%)
Metabolic encephalopathy	1/681 (0.1%)		0/342 (0%)
Nerve root compression	1/681 (0.1%)		1/342 (0.3%)
Paraesthesia	1/681 (0.1%)		0/342 (0%)
Paraparesis	0/681 (0%)		2/342 (0.6%)
Paralpegia	0/681 (0%)		2/342 (0.6%)
Parkinson's disease	1/681 (0.1%)		0/342 (0%)
Peripheral motor neuropathy	1/681 (0.1%)		0/342 (0%)
Presyncope	1/681 (0.1%)		1/342 (0.3%)
Quadriparesis	1/681 (0.1%)		0/342 (0%)
Sciatica	1/681 (0.1%)		0/342 (0%)
Sensorimotor disorder	0/681 (0%)		1/342 (0.3%)
Sensory loss	0/681 (0%)		1/342 (0.3%)
Somnolence	1/681 (0.1%)		0/342 (0%)
Spinal cord compression	14/681 (2.1%)		8/342 (2.3%)
Spinal cord paralysis	0/681 (0%)		1/342 (0.3%)
Stupor	1/681 (0.1%)		0/342 (0%)
Syncope	5/681 (0.7%)		2/342 (0.6%)
Radiculitis	0/681 (0%)		1/342 (0.3%)
Psychiatric disorders
Agitation	1/681 (0.1%)		0/342 (0%)
Anxiety	1/681 (0.1%)		1/342 (0.3%)
Confusional state	7/681 (1%)		0/342 (0%)
Delirium	2/681 (0.3%)		1/342 (0.3%)
Depression	0/681 (0%)		1/342 (0.3%)
Renal and urinary disorders
Bladder dysfunction	0/681 (0%)		1/342 (0.3%)
Bladder outlet obstruction	0/681 (0%)		1/342 (0.3%)
Calculus bladder	1/681 (0.1%)		0/342 (0%)
Dysuria	0/681 (0%)		1/342 (0.3%)
Haematuria	5/681 (0.7%)		3/342 (0.9%)
Hydronephrosis	5/681 (0.7%)		4/342 (1.2%)
Hydroureter	1/681 (0.1%)		0/342 (0%)
Nephrolithiasis	1/681 (0.1%)		0/342 (0%)
Prerenal failure	1/681 (0.1%)		0/342 (0%)
Renal failure	2/681 (0.3%)		3/342 (0.9%)
Renal failure acute	12/681 (1.8%)		4/342 (1.2%)
Renal impairment	1/681 (0.1%)		1/342 (0.3%)
Ureteric stenosis	1/681 (0.1%)		0/342 (0%)
Urethral obstruction	1/681 (0.1%)		0/342 (0%)
Urinary bladder haemorrhage	1/681 (0.1%)		0/342 (0%)
Urinary retention	7/681 (1%)		1/342 (0.3%)
Urinary tract disorder	1/681 (0.1%)		0/342 (0%)
Urinary tract obstruction	4/681 (0.6%)		1/342 (0.3%)
Reproductive system and breast disorders
Pelvic pain	1/681 (0.1%)		0/342 (0%)
Penile swelling	1/681 (0.1%)		0/342 (0%)
Perineal pain	0/681 (0%)		1/342 (0.3%)
Scrotal swelling	1/681 (0.1%)		0/342 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/681 (0.3%)		0/342 (0%)
Chronic obstructive pulmonary disease	0/681 (0%)		1/342 (0.3%)
Dysphonia	2/681 (0.3%)		0/342 (0%)
Dyspnoea	10/681 (1.5%)		3/342 (0.9%)
Emphysema	1/681 (0.1%)		0/342 (0%)
Epistaxis	5/681 (0.7%)		2/342 (0.6%)
Haemoptysis	1/681 (0.1%)		0/342 (0%)
Lung disorder	1/681 (0.1%)		0/342 (0%)
Pleural effusion	9/681 (1.3%)		3/342 (0.9%)
Pneumonia aspiration	1/681 (0.1%)		0/342 (0%)
Pneumothorax	4/681 (0.6%)		0/342 (0%)
Pulmonary embolism	42/681 (6.2%)		3/342 (0.9%)
Pulmonary oedema	1/681 (0.1%)		0/342 (0%)
Respiratory failure	3/681 (0.4%)		1/342 (0.3%)
Skin and subcutaneous tissue disorders
Angioedema	1/681 (0.1%)		0/342 (0%)
Decubitus ulcer	1/681 (0.1%)		1/342 (0.3%)
Palmar-plantar erythrodysaesthesia syndrome	3/681 (0.4%)		0/342 (0%)
Rash	1/681 (0.1%)		0/342 (0%)
Rash macular	1/681 (0.1%)		0/342 (0%)
Skin ulcer	2/681 (0.3%)		0/342 (0%)
Stasis dermatitis	1/681 (0.1%)		0/342 (0%)
Vascular disorders
Aortic aneurysm rupture	1/681 (0.1%)		0/342 (0%)
Arterial occlusive disease	1/681 (0.1%)		0/342 (0%)
Circulatory collapse	0/681 (0%)		1/342 (0.3%)
Deep vein thrombosis	11/681 (1.6%)		3/342 (0.9%)
Hypertension	7/681 (1%)		2/342 (0.6%)
Hypertensive crisis	1/681 (0.1%)		1/342 (0.3%)
Hypotension	4/681 (0.6%)		2/342 (0.6%)
Malignant hypertension	1/681 (0.1%)		0/342 (0%)
Orthostatic hypotension	3/681 (0.4%)		0/342 (0%)
Peripheral arterial occlusive disease	1/681 (0.1%)		1/342 (0.3%)
Peripheral ischaemia	0/681 (0%)		1/342 (0.3%)
Shock haemorrhagic	0/681 (0%)		1/342 (0.3%)
Venous haemorrhage	1/681 (0.1%)		0/342 (0%)
Other (Not Including Serious) Adverse Events
	Cabozantinib		Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	675/681 (99.1%)		332/342 (97.1%)
Blood and lymphatic system disorders
Anaemia	203/681 (29.8%)		111/342 (32.5%)
Thrombocytopenia	42/681 (6.2%)		20/342 (5.8%)
Endocrine disorders
Hypothyroidism	94/681 (13.8%)		1/342 (0.3%)
Gastrointestinal disorders
Abdominal pain	76/681 (11.2%)		16/342 (4.7%)
Abdominal pain upper	43/681 (6.3%)		16/342 (4.7%)
Constipation	227/681 (33.3%)		100/342 (29.2%)
Diarrhoea	349/681 (51.2%)		68/342 (19.9%)
Dry mouth	65/681 (9.5%)		11/342 (3.2%)
Dyspepsia	58/681 (8.5%)		6/342 (1.8%)
Dysphagia	41/681 (6%)		0/342 (0%)
Gastrooesophageal reflux disease	37/681 (5.4%)		7/342 (2%)
Nausea	390/681 (57.3%)		102/342 (29.8%)
Stomatits	127/681 (18.6%)		8/342 (2.3%)
Vomiting	271/681 (39.8%)		67/342 (19.6%)
General disorders
Asthenia	228/681 (33.5%)		63/342 (18.4%)
Fatigue	338/681 (49.6%)		119/342 (34.8%)
General physical health deterioration	47/681 (6.9%)		13/342 (3.8%)
Muscosal inflammation	134/681 (19.7%)		9/342 (2.6%)
Oedema peripheral	101/681 (14.8%)		43/342 (12.6%)
Pain	56/681 (8.2%)		33/342 (9.6%)
Pyrexia	67/681 (9.8%)		36/342 (10.5%)
Infections and infestations
Urinary tract infection	71/681 (10.4%)		29/342 (8.5%)
Investigations
Alanine aminotransferase increased	56/681 (8.2%)		10/342 (2.9%)
Aspartate aminotransferase increased	70/681 (10.3%)		14/342 (4.1%)
Weight decreased	237/681 (34.8%)		41/342 (12%)
Metabolism and nutrition disorders
Decreased appetite	407/681 (59.8%)		99/342 (28.9%)
Dehydration	38/681 (5.6%)		15/342 (4.4%)
Hypocalcaemia	50/681 (7.3%)		20/342 (5.8%)
Hypokalaemia	69/681 (10.1%)		9/342 (2.6%)
Hypomagnesaemia	36/681 (5.3%)		3/342 (0.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	91/681 (13.4%)		50/342 (14.6%)
Back pain	115/681 (16.9%)		64/342 (18.7%)
Bone pain	109/681 (16%)		63/342 (18.4%)
Muscle spasms	48/681 (7%)		20/342 (5.8%)
Muscular weakness	48/681 (7%)		22/342 (6.4%)
Musculoskeletal pain	43/681 (6.3%)		37/342 (10.8%)
Pain in extremity	98/681 (14.4%)		36/342 (10.5%)
Nervous system disorders
Dizziness	48/681 (7%)		19/342 (5.6%)
Dysgeusia	175/681 (25.7%)		16/342 (4.7%)
Headache	87/681 (12.8%)		14/342 (4.1%)
Psychiatric disorders
Depression	42/681 (6.2%)		11/342 (3.2%)
Insomnia	53/681 (7.8%)		28/342 (8.2%)
Respiratory, thoracic and mediastinal disorders
Cough	52/681 (7.6%)		15/342 (4.4%)
Dysphonia	180/681 (26.4%)		21/342 (6.1%)
Dyspnoea	135/681 (19.8%)		46/342 (13.5%)
Epistaxis	37/681 (5.4%)		9/342 (2.6%)
Skin and subcutaneous tissue disorders
Dry skin	53/681 (7.8%)		8/342 (2.3%)
Palmar-plantar erythrodysaesthesia syndrome	200/681 (29.4%)		5/342 (1.5%)
Vascular disorders
Hypertension	191/681 (28%)		38/342 (11.1%)
Hypotension	36/681 (5.3%)		13/342 (3.8%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Our agreements with investigators vary; constant is our right to review results communications prior to public release, and embargo communications for a period of ≤60 days from submittal for review. We do not prohibit investigators from publishing, but we may require previously undisclosed confidential information, other than study results, to be removed from publications, and single-center publications are postponed until after publication of the trial's primary multicenter publication.