Original research

Efﬁcacy, quality of life, and safety of cabazitaxel in Canadian

metastatic castration-resistant prostate cancer patients treated or not

with prior abiraterone

Fred Saad, MD, FRCS; Eric Winquist, MD, MSc; Stacey Hubay, MD; Scott Berry, MD, MHSc;

Hazem Assi, MD; Eric Levesque, MD, PhD; Nathalie Aucoin, MD; Piotr Czaykowski, MD, MSc;

Jean-Baptiste Lattouf, MD; Karine Alloul, BPharm, MSc; John Stewart, MSc , Srikala S. Sridhar, MD, MSc

CRCHUM/Université de Montréal, Montreal, QC, Canada; London Health Sciences Centre, London, ON, Canada; Grand River Regional Cancer Centre, Kitchener, ON, Canada; Sunnybrook, Odette Cancer

Centre, Toronto, ON, Canada; Horizon Health Network, Moncton, NB, Canada; CHUQ Hôtel-Dieu de Québec, Quebec City, QC, Canada; Cité-de-la-Santé Hospital, Laval, QC, Canada; CancerCare Manitoba,

Winnipeg, MB, Canada; Sanoﬁ-aventis Canada Inc., Montreal, QC, Canada; Princess Margaret Hospital, Toronto, ON, Canada.

Cite as: Can Urol Assoc J 2016;10(3-4):102-9. http://dx.doi.org/10.5489/cuaj.3470

Introduction

Prostate cancer is a heterogeneous disease presenting with

See related article on page 111.

inter- and intra-individual variations due to molecular

heterogeneity, which impacts on patients’ responsiveness

to therapy. Sensitivity to androgen blockade varies based

on quantitative and qualitative characteristics of androgen

Abstract

Introduction: In the TROPIC study, cabazitaxel improved overall

survival in abiraterone-naïve metastatic castration-resistant prostate

cancer (mCRPC) patients post-docetaxel. To evaluate cabazitaxel

in routine clinical practice, an international, single-arm trial was

conducted. Efﬁcacy, safety, and quality of life (QoL) data were

collected from Canadian patients enrolled. Overall survival and

progression-free survival were not collected as part of this study.

Importantly, prior abiraterone use was obtained and its impact on

clinical parameters was examined.

Methods: Sixty-one patients from nine Canadian centres were

enrolled, with prior abiraterone use known for 60 patients. Prostate-

speciﬁc antigen (PSA) response rate, safety, and impact on QoL life

were analyzed as a function of prior abiraterone use.

Results: Overall, 92% of patients were ECOG 0/1, 88% had bone

metastases, and 25% visceral metastases. Patients treated with-

out prior abiraterone (NoPriorAbi) (n=35, 58%) and with prior

abiraterone (PriorAbi) (n=25, 42%) had similar baseline char -

acteristics, except for age and prior cumulative docetaxel dose.

Median number of cabazitaxel cycles received was similar between

groups (NoPriorAbi=6, PriorAbi=7), as was PSA response rate

receptor (AR) expression. In patients with recurrent or

metastatic prostate cancer, androgen-deprivation therapy

2,3

(ADT) remains the mainstay of treatment. However, it is not

curative and inevitably androgen-independent progression

occurs. Patients are then categorized as having castration-

resistant prostate cancer (CRPC).

In patients with mCRPC, docetaxel was the ﬁrst agent

approved that demonstrated a survival beneﬁt. It has been

the ﬁrst-line treatment of choice for over a decade. However,

in the last few years, several novel agents have provided new

hope for patients with mCRPC. Hormonal agents, such

as abiraterone acetate, which induces remission of prostate

cancer via CYP17 inhibition of extragonadal and intratu-

moural androgen synthesis, has been shown in randomized

trials to improve overall survival when given either before

or after docetaxel. Similarly, the hormonal agent enzalut-

amide, which targets the androgen receptor, has also shown

a survival benefit both pre- and post-docetaxel. From a

chemotherapy standpoint, cabazitaxel is a novel taxane with

(

NoPriorAbi=36.4%, PriorAbi=45.0%, p=0.54). Almost one-third

31%) of patients received prophylactic granulocyte colony-stimu-

in vitro efﬁcacy in docetaxel resistant cell lines. In a large,

lating factors. Most frequent Grade 3/4 toxicities were neutropenia

14.8%); anemia, febrile neutropenia, fatigue (each at 9.8%); and

randomized trial (TROPIC), cabazitaxel improved overall

survival compared to mitoxantrone in men with mCRPC

(

diarrhea (8.2%). No treatment-related adverse event leading to

death was observed. QoL and pain were improved with no differ-

ence seen between groups. Treatment discontinuation was mainly

due to disease progression (45.9%) and adverse events (32.8%).

Conclusions: In routine clinical practice, cabazitaxel’s risk-beneﬁt

ratio in mCRPC patients previously treated with docetaxel seems

to be maintained independent of prior abiraterone use.

progressing on or after ﬁrst-line docetaxel.

One of the key challenges currently facing clinicians

treating mCRPC is not a lack of novel treatment options,

but rather knowing how best to sequence the novel agents

to maximize beneﬁt. While we await large, prospective,

randomized trials addressing sequencing questions, we

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can look at our smaller prospective trials to better under-

stand the efﬁcacy and safety of the novel treatments when

used in sequence. In the current study, mCRPC patients

received cabazitaxel post-docetaxel in routine clinical prac-

tice. Prostate-speciﬁc antigen (PSA) response rates, safety,

and quality of life (QoL) data, as well as prior abiraterone

use were collected on the Canadian cohort. Exploratory

hypothesis-generating analyses have been conducted to

evaluate the impact of prior abiraterone use on these key

clinical outcomes, thus, providing preliminary information

and adding to a growing body of evidence on how to best

sequence these treatments.

Inclusion and exclusion criteria

Patients having mCRPC were included in the study if they

were 18 years of age or older, had an Eastern Cooperative

Oncology Group (ECOG) performance status of 0‒2, had

progressed during or after docetaxel, had ongoing surgical

or medical castration, had adequate bone marrow, liver and

renal function, had signed informed consent, and had a life

expectancy of three months or longer.

Patients were excluded as per the TROPIC study exclusion

criteria. The study was approved by an Independent Ethics

Committee at each site in accordance with the Declaration

of Helsinki, Good Clinical Practices. All patients signed

informed consent before study entry.

Methods

Statistical analysis

Design and objectives

A formal sample size calculation was not done for the

Canadian portion of the study, as it represented a subgroup

of a larger international trial. The safety population consisted

of patients who had received any cabazitaxel.

This study reports on post-hoc analyses conducted on

Canadian patients enrolled in the Cabazitaxel International

Expanded-Access Program (EAP) study (NCT01254279). This

prospective, single-arm, open-label, multicentre clinical trial

intended to provide early access to cabazitaxel for patients

with mCRPC progressing on or after docetaxel (a similar

patient population to the TROPIC study). In addition, safety

data were collected and graded according to the National

Cancer Institute Common Terminology Criteria for Adverse

Events, Version 4.0 (NCI CTCAE v. 4.0), of cabazitaxel. Only

in Canada, efﬁcacy data based on PSA response and QoL data

were collected and evaluated based on prior abiraterone use.

PSA response was measured and collected by the investiga-

tor, as per his/her clinical practice, at baseline and at each

cycle. Overall survival and progression-free survival were

not collected as part of this study. Patients were treated until

disease progression, death, unacceptable toxicity, investiga-

tor’s decision, or up to 10 cycles. Patients were followed for

up to 30 days after the last administration of study treatment.

PSA-evaluable patients were patients who had a base-

line and on-treatment assessments for PSA. PSA response

was deﬁned as per the Prostate Cancer Working Group 2

guidelines (PCWG2), which is a ≥50% decline in PSA from

baseline maintained for at least three weeks (two consecu-

tive cycles three weeks apart) and measured by the same lab-

oratory, and without evidence of other disease progression

documented at time of conﬁrmatory values. PSA progression

was deﬁned as a ≥25% increase in PSA and an absolute

increase of ≥2 ng/mL in PSA from the nadir in patients with

a decline following baseline. In patients without a decline

following baseline, PSA progression was deﬁned as a ≥25%

increase in PSA and an absolute increase of ≥2 ng/mL in

PSA after 12 weeks of treatment.

Prostate cancer-speciﬁc QoL data was collected using

the Functional Assessment of Cancer Therapy – Prostate

(

FACT-P) self-administered questionnaire. This validated

Patient treatment schedule

questionnaire is frequently used to assess QoL in men

with prostate cancer. A higher score on the FACT-P and its

subscales indicates better QoL. Baseline assessment with

the questionnaire was performed and patients were asked to

complete the questionnaire at each clinic visit, before visit-

ing the physician and before treatment administration, and

at the followup visit after the last treatment cycle. The QoL

population consisted of patients having responded to at least

80% of the items in the FACT-P questionnaire at baseline

and on-treatment. For the QoL analyses, a t-test compared

the percent of patients that showed an improvement by a

minimally clinically important difference (Table 1).

Patients received cabazitaxel at a dose of 25 mg/m during a

one-hour intravenous (IV) infusion on Day 1 of every three-

week cycle. This was given with prednisone or prednisolone

at a dose of 10 mg orally daily. One dose reduction (to 20

mg/m ) per patient was permitted throughout the study. Dose

delays not exceeding two weeks were permitted.

Primary prophylaxis with granulocyte colony-stimulating

factor (G-CSF) was considered (but not obligatory) in patients

with high-risk clinical features (age ≥65 years, poor per-

formance status, previous episodes of febrile neutropenia,

extensive prior radiation ports, poor nutritional status, or

other serious comorbidities) that could predispose patients

to increased complications from neutropenia.

Pain response rate was evaluated using the McGill-

Melzack Present Pain Intensity Index (PPI) and analgesic

use was derived from consumption normalized to morphine

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Table 1. Quality of life values

equivalents, as in TROPIC. The percentage of patients meet-

ing the pain response rate criteria are speciﬁed in Table 1.

Results are presented for the safety, QoL, and PSA-evaluable

populations and variations in the number of patients between

study parameters was due to the fact that data were not

always available for each individual patient.

Abiraterone use was obtained during the trial as part of

the patients’ medical history. A post-hoc analysis was con-

ducted in Canadian patients after the database was locked

to evaluate the impact of the prior use of abiraterone on

cabazitaxel’s efﬁcacy assessed based on PSA response, QoL,

and safety. Unpaired t-tests were used to compare par -

ameters between cabazitaxel patients in the PriorAbi and

NoPriorAbi groups.

Prior use of

abiraterone

Patients (%)

Parameters n (%)

p value

(n=53)^¶

No (n=33) Yes (n=20)

FACT-P ≥16

7 (13.0)

3 (9.1)

4 (20.0)

0.2807

points*

FACT-P ≥10

points*

14 (25.9)

6 (18.2)

10 (30.3)

15 (46.9)

8 (40.0)

10 (50.0)

11 (57.9)

0.1454

0.2151

0.7011

FACT-P ≥6 points*

20 (37.0)

PCS subscale ≥2

points*

6 (50.0)

2 (23.1)

PCS pain subscale

≥2 points*

7 (21.9)

3 (20.0)

5 (26.3)

1 (25.0)

0.8505

0.7425

Pain response rate^‡

4 (21.1)

*Minimally clinically important difference observed on two consecutive cycles where an

increase in score on the FACT-P instrument and its subscales indicates improvement in

quality of life.¶ For the FACT-P questionnaire, an evaluable patient is deﬁned as a patient

who responds to at least 80 % of the items. FACT–P is a 39-item questionnaire that consists

of FACT–G (general), a 27-item self-report questionnaire that measures general health-

related quality of life in cancer patients, and the Prostate Cancer Subscale (PCS), a 12-item

subscale speciﬁcally designed to measure prostate cancer-speciﬁc quality of life. The

FACT–P total score includes the FACT–G and the PCS. The FACT–P PCS pain-related score

includes four questions from the FACT–P interrogating pain speciﬁcally. ‡Pain response was

established only for patients with median present pain intensity (PPI) score of 2 or more or

mean analgesic score (AS) of 10 points or more at baseline, or both, and was deﬁned as a

two-point or greater reduction from baseline median PPI score without an increased AS or

a decrease of 50% or more in the AS without an increase in the PPI score, maintained for at

least three weeks. FACT-P: Functional Assessment of Cancer Therapy – Prostate.

Results

Patient and disease characteristics

A total of 61 Canadian patients were enrolled in the inter-

national EAP from nine Canadian sites between May 2011

and February 2012. Of these 61 patients, prior abirater -

one exposure status was known in 60 patients who were

divided into two groups: NoPriorAbi (n=35, 58.3%) and

PriorAbi (n=25, 41.7%). Patients’ baseline characteristics,

disease and treatment history are presented in Table 2. The

median age was 65 years with 18% of patients being 75 or

older. All patients were previously treated with docetaxel

Exposure to cabazitaxel

Patients received a median number of cabazitaxel cycles of

six (range 1‒27). The median cumulative dose of cabazitaxel

was 259.0 mg/m (range 43.0‒1269.0 mg/m ). At baseline

(Table 2). Most patients (91.8%) had an ECOG performance

all patients received 25 mg/m cabazitaxel. Main reasons

status of 0 or 1. Median time since mCPRC diagnosis was

for treatment discontinuation were disease progression in

45.9% (NoPriorAbi=48.6%, PriorAbi=44.0%) and adverse

events in 32.8% (NoPriorAbi=25.7%, PriorAbi=40.0%).

.2 years (range 0.4‒18.0). The median time from initial

diagnosis of prostate cancer was 6.3 years (range 0.8‒21.5).

The median cumulative dose of docetaxel was 750 mg/m

(

range 136‒3406 mg/m ). The median number of docetaxel

Efﬁcacy

cycles was eight (range 3‒24). The median time from last

docetaxel dose to ﬁrst cabazitaxel cycle was 7.82 months

PSA response, deﬁned as a ≥50% decline in PSA from base-

line maintained for at least three weeks and evaluable for 53

patients, was achieved in 39.6% of overall patients, 36.4% of

patients without the prior use of abiraterone, and 45.0% with

prior abiraterone use (p=0.54). Waterfall plots of best PSA

response are presented in Figs. 1A and 1B. The median time

to PSA progression, evaluable for 53 patients, was 5.1 months

for no prior abiraterone use compared to 4.9 months for prior

abiraterone use (hazard ratio [HR] 0.63; p=0.26) (Fig. 2).

(

range 0.9‒56.8) with 41.0% of patients receiving the ﬁrst

cabazitaxel cycle within six months of their last docetaxel

dose. The time between the last docetaxel dose and pro-

gression was ≥6 months in 45.9% (28/61) of patients, 3‒6

months in 18.0% (11/61) of patients, <3 months in 24.6%

of patients (15/61), and 11.5% (7/61) of patients received

their last docetaxel dose after progression. More than half of

the patients presented with two or more metastatic sites and

nearly 25% presented with visceral metastases. Signiﬁcantly,

more patients received a higher cumulative dose of docetaxel

in the group with no prior use of abiraterone. Patient charac-

teristics were similar between the NoPriorAbi and PriorAbi

groups except for age and cumulative docetaxel dose.

NoPriorAbi patients tended to be younger and received a

higher cumulative docetaxel dose (Table 2).

Quality of life

The proportions of the patients reaching a minimal import-

ant improvement on the FACT-P total score, Prostate Cancer

Subscale (PCS) and PCS pain subscale scores were similar

in both groups regardless of prior abiraterone use, as were

the pain response rates (Table 1).

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Table 2. Patient characteristics (safety population)

All patients

n=61)

Prior use of abiraterone

Characteristics

p value

(

No (n=35)

Yes (n=25 )

†

Age, yr, median (range)

Age, n (%)

65 (42–81)

64 (42–78)

69 (47–81)

0.0253*

65 years

27 (44.3)

23 (37.7)

11 (18.0)

18 (51.4)

15 (42.9)

2 (5.7)

9 (36.0)

8 (32.0)

65 years to <75 years

0.0310**

1.0000**

≥75 years

ECOG performance status, n (%)

18 (29.5)

38 (62.3)

5 (8.2)

11 (31.4)

20 (57.1)

4 (11.4)

6 (24.0)

18 (72.0)

1 (4.0)

Time since diagnosis, years, median (range)

Initial

6.3 (0.8–21.5)

2.2 (0.4–18.0)

5.7 (0.8–18.8)

2.1 (0.4–6.6)

6.6 (1.6–21.3)

2.6 (1.0–18.0)

0.1850*

0.2769*

mCRPC

Number of metastatic sites, n (%)

26 (42.6)

35 (57.4)

16 (45.7)

19 (54.3)

10 (40.0)

15 (60.0)

0.6623**

≥2

≠

Location of metastatic sites , n (%)

Bones

54 (88.5)

15 (24.6)

23 (37.7)

6 (9.8)

29 (82.9)

8 (22.9)

15 (42.9)

4 (11.4)

24 (96.0)

7 (28.0)

2 (8.0)

0.1211**

0.6529**

0.2430**

0.6652

Visceral

Lymph nodes

Other

Time between last docetaxel dose and progression, n (%)

0 months

7 (11.5)

15 (24.6)

11 (18.0)

28 (45.9)

6 (17.1)

10 (28.6)

5 (14.3)

14 (40.0)

1 (4.0)

4 (16.0)

6 (24.0)

14 (56.0)

to <3 months

to <6 months

0.054**

At least 6 months

Type of progression, n (%)

Bone scan and measurable lesions

Clinical progression

29 (47.5)

15 (24.6)

52 (85.2)

19 (54.3)

6 (17.1)

10 (40.0)

9 (36.0)

0.2790**

0.0991**

0.5855**

Increased PSA

29 (82.9)

22 (88.0)

Type of castration, n (%)

Medical

56 (91.8)

5 (8.2)

33 (94.3)

2 (5.7)

22 (88.0)

3 (12.0)

Surgical

0.3891**

Cumulative docetaxel dose (mg/m2) by category, n (%)⁺

225

1 (1.7)

10 (16.9)

0 (0.0)

5 (14.3)

1 (4.3)

5 (21.7)

≥225–450

≥450–675

≥675–900

≥900

11 (18.6)

4 (11.4)

7 (30.4)

0.0486**

0.2415**

19 (32.2)

14 (40.0)

5 (21.7)

18 (30.5)

12 (34.3)

5 (21.7)

Median (range)

750 (136–3406)

750 (254–2250)

602 (136–3406)

†One patient was withdrawn from the study analysis due to lack of information on his prior use of abiraterone. ≠Prevalence of >5%. +The dose of docetaxel for two patients was missing.

*p value based on Student t-est. ** p value based on Cochran Mantel Haenszel statistic. ECOG: Eastern Cooperative Oncology Group; mCRPC: metastatic castration-resistant prostate cancer;

PSA: prostate-speciﬁc antigen.

overall. This rate was 60% (21/35) in patients with no prior

use of abiraterone and 80% (20/25) among prior abiraterone

users (p=0.16). Most frequent Grade 3/4 toxicities were neu-

tropenia (14.8%); anemia, febrile neutropenia, and fatigue

(each at 9.8%); and diarrhea (8.2%). G-CSF was adminis-

tered prophylactically at Cycle 1 in 19 patients (31.1%).

No treatment-related adverse event leading to death was

observed.

Safety

Overall, treatment discontinuation due to treatment-emer-

gent adverse events (TEAEs) was 32.8% (NoPriorAbi=25.7%,

PriorAbi=40.0%; p=0.27) (Table 3). TEAEs of any grade were

observed in all of the 61 patients (100%). TEAEs of Grade

and more were observed in 68.9% (42/61) of patients

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-25

-50

-75

-100

50% threshold

-50% threshold

100

Figs. 1A,B. Waterfall plot of best prostate-speciﬁc antigen response to cabazitaxel therapy in each patient (A) with and (B) without prior

exposure to abiraterone.

Discussion

maintained for eight weeks after chemotherapy discon -

,11

tinuation. There was no signiﬁcant difference in median

number of treatment cycles among patients who had prior

use of abiraterone (six cycles, range 1‒27) or not (seven

cycles, range 1‒13) (Table 4). These results are similar to

the number of treatment cycles in the TROPIC study (six

In this study, we evaluated the efﬁcacy, safety, and impact on

QoL of cabazitaxel administered to mCRPC patients enrolled

in the Canadian arm of an international, expanded-access

program. Importantly, we conducted exploratory analyses

to provide further insight into whether or not prior abirater-

one use impacted key outcome measures, namely efﬁcacy,

safety, QoL. Canada was the only country to collect PSA

and FACT-P QoL data.

From an efficacy perspective, we observed that the

activity of cabazitaxel seems to be maintained in the post-

abiraterone setting, despite patients having undergone more

treatment regimens, as demonstrated by the PSA response,

number of cycles, and QoL data. A ≥50% PSA decline

was achieved in nearly 40% of patients, both in those

who received prior abiraterone (45.0% of patients) or not

cycles, range 3‒10). Overall, these results suggest that the

use of cabazitaxel after prior abiraterone appears efﬁcacious.

These results should, however, be appraised in the context of

important limitations, which include a limited sample size,

non-randomized design, and post-hoc analyses.

Overall, we found the frequency of adverse events Grade

3 or higher in patients that received cabazitaxel was 68.9%.

This frequency was 80% in patients with prior abiraterone

use and 60% in patients with no prior abiraterone use

(p=0.16). The limited sample size in both groups prevents

conclusions on the statistical signiﬁcance of this difference.

Patient characteristics, however, may have inꢀuenced this

numerical difference. Patients with prior abiraterone were

signiﬁcantly older and presented with numerically worse

ECOG performance status than patients without prior abir-

aterone use. These observations are not surprising consid-

ering that cabazitaxel would be administered as a later line

of therapy in patients that received prior abiraterone.

(

36.4%) (p=0.5371). This is in line with European reports,

where 35% of 79 patients from France and 39% of the

9 patients from U.K. achieved a ≥50% PSA decline with

cabazitaxel following AR targeted therapies. Additionally,

our overall 40.7% of PSA response is similar to the TROPIC

study (39.2%) and to the German EAP report, where 37.6%

(

35/93) of patients showed a ≥50% PSA reduction that was

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Fig. 2. Kaplan-Meier curves for time to prostate-speciﬁc antigen progression (months) with cabazitaxel by prior exposure to abiraterone.

Most importantly, the adverse events were manageable

with a reported frequency of febrile neutropenia of 9.8%, and

Grade 3 or higher neutropenia of 14.8%. G-CSF was used

as primary or secondary prophylaxis in 31% of patients. In

the TROPIC study, more post-docetaxel cabazitaxel patients

compared to mitoxantrone patients presented with hema-

tological Grade 3 or higher adverse events, with Grade ≥3

clinical practice has a manageable safety proﬁle that does not

appear to be impacted by the prior use of abiraterone acetate.

However, this conclusion is limited by the small sample size

in each of these subgroups and further research is warranted.

9,20

With the recent results in pre-

and post-chemo-

1,22

settings of the novel hormonal therapies, and

therapy

the possible emergence of new hormonal agents to treat

neutropenia affecting 82% of patients. It is important to note

mCRPC, the optimal sequencing of these agents remains

that in the TROPIC trial, prophylactic G-CSF use was not

a major issue. Some studies have suggested that giving two

agents sequentially that both target the androgen signaling

pathway (i.e., abiraterone followed by enzalutamide or the

permitted during the ﬁrst cycle, contrary to the EAP. The

safety proﬁle of cabazitaxel in the Canadian EAP patients is

consistent with the ones reported by our European counter-

Heidenreich et al showed that in Germany,

opposite) may not be the best option for mCRPC patients

because of cross-resistance.

parts.¹

1,14-18

23-26

In the study by Loriot et al,²³

cabazitaxel in routine clinical practice in mCRPC patients

post-docetaxel had a manageable toxicity proﬁle. Grade ≥3

only three of the 38 patients (8%) who received abiraterone

following progression on both enzalutamide and docetaxel

attained a PSA response (≥50% decline in PSA conﬁrmed

after ≥4 weeks). Similarly, in the study by Bianchini et al,²⁴

only 12.8% of the 39 patients achieved a PSA response

when they received enzalutamide following progression

on both abiraterone and docetaxel. For treatment sequen-

ces involving enzalutamide or abiraterone as a second-line

agent following the opposite agent, several other studies

have reported that 17‒28% of patients achieved a PSA

neutropenia occurred in 7.2% of patients (G-CSF was admin-

istered prophylactically in 13.5% of patients at Cycle 1).

Other published EAP reports have shown the rates of Grade

4,15,18

prophylactic use of G-CSF in 16.3‒62.4%

or higher neutropenia range from 33.9–4.1%

with

4,15,18

of patients.

Non-hematological adverse events of Grade ≥3 occurred at

a similar manageable frequency in our study compared to

1,14-18

and the TROPIC trial. Overall,

previous EAP reports

this EAP study has demonstrated that cabazitaxel in routine

6-34

A report from Schnadig et al showed that

response.

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Table 3. Treatment-emergent adverse events

patients who received cabazitaxel third-line if they received

abiraterone second-line.

(safety population)

Grade ≥3

Patients (%)

Prior use of abiraterone

No (n=35) Yes (n=25)

Treatment-emergent

adverse events*

Despite the suggested effect of cabazitaxel on the andro-

gen receptor pathway, it appears that cabazitaxel may be

less likely to be affected by prior hormonal therapy treat-

ment. In vitro studies had shown that cabazitaxel was able

to decrease cell viability in both enzalutamide-resistant and

enzalutamide-sensitive cells, but abiraterone did not show

the same decrease in cell viability following enzalutamide.¹²

It appears that cabazitaxel has its effects on prostate can-

cer cells mainly via pathways independent of the androgen

receptor, which could reduce the cross-resistance phenom-

(n=61)

Patients with TEAEs

Hematological TEAEs

Neutropenia

42 (68.9)

21 (60.0)

20 (80.0)^†

9 (14.8)

6 (9.8)

4 (11.4)

3 (8.6)

3 8.6)

5 (20.0)

3 (12.0)

Anemia

Febrile neutropenia

White blood cell count

decreased

(4.9)

2 (5.7)

1 (4.0)

Non-hematological TEAEs

Fatigue

enon observed with hormonal therapies. This would be

a viable explanation as to why prior abiraterone did not

impact cabazitaxel efficacy; and similar PSA responses

were reported in other studies when cabazitaxel was used

6 (9.8)

5 (8.2)

3 (4.9)

4 (6.6)

3 (4.9)

1(1.6)

3 (8.6)

0 (0.0)

1 (2.9)

2 (5.7)

1 (2.9)

2 (5.7)

1 (2.9)

0 (0.0)

3 (12.0)

2 (8.0)

3 (12.0)

1 (4.0)

0 (0.0)

1 (4.0)

2 (8.0)

Diarrhea

Back pain

Dehydration

Spinal cord compression

Nausea

2,13

post-hormonal therapies in mCRPC patients.

In conclusion, this EAP study, although limited by its small

sample size, provides additional data on the efﬁcacy and safe-

ty of cabazitaxel in mCRPC patients previously treated with

docetaxel, with or without prior abiraterone use. This is also

the ﬁrst time FACT-P data is reported relative to cabazitaxel

and in relation to previous exposure to abiraterone. As CRPC

Vomiting

Cellulitis

Sepsis

Pain in extremity

Asthenia

2 (3.3)

6-40

remains a major health concern worldwide

and numer-

Pulmonary embolism

ous new therapeutic agents are now available,⁵research

to understand what treatment should be given at what time

remains important to optimize patient management.

Renal failure acute

*TEAEs with a frequency ≥2% for Grade ≥3 adverse events. TEAEs are classiﬁed based on

the frequency of grade ≥3 TEAEs. †p=0.16. Signiﬁcance of speciﬁc hematological and non-

hematological TEAEs was not assessed as analyses would be underpowered due to the

small number of events in each group. TEAE: treatment-emergent adverse events.

Competing interests: This study was sponsored by Sanofi. This study is registered on

clinicaltrial.gov as NCT01254279.

more patients reached a third-line treatment if they received

docetaxel followed immediately by cabazitaxel, compared

to docetaxel followed by abiraterone. This retrospective

analysis in 667 post-docetaxel mCRPC patients showed

that 31% of patients who received cabazitaxel second-line

received abiraterone in third-line, compared to only 12% of

Dr. Saad has been an Advisory Board member for Janssen and Sanoﬁ; and has received research

funding, as well as honoraria from Sanoﬁ. Dr. Berry has been an Advisory Board member for and

received honoraria from Sanoﬁ. Dr. Levesque has been an Advisory Board member for Astellas,

Table 4. Cabazitaxel exposure

Characteristics

All patients

N=61)

6.0 (1–27)

Prior use of abiraterone

p value

(

No (n=35)

Yes (n=25)

7 (1–13)

Cycles of cabazitaxel, n, median (range)

6 (1–27)

268.8 (43–1269)

10 (28.6)

0.2517

0.1762

0.4535

0.6991

0.4118

Cumulative dose of cabazitaxel, median (mg/m²)

Patients receiving more than 10 cycles of cabazitaxel, n (%)

Relative dose intensity, median*

259.0 (43–1269)

15 (24.6)

259.0 (45–550)

5 (20.0)

100 (80–100)

28 (50.0)**

100 (82–100)

16 (45.7)

100 (80–100)

12 (57.1)

Dose delay, n (%)

Dose delays due to:

Hematotoxicity

Non-hematotoxicity

Other

(21.4)

(14.3)

1 (6.3)

2 (12.5)

13 (81.2)

5 (41.7)

2 (16.7)

5 (41.7)

0.3157

0.3957

18 (64.3)

Dose reduction, n (%)

15 (26.8)**

8 (22.9)

7 (33.3)

Dose reduction due to:

Hematotoxicity

Non-hematotoxicity

Other

6 (40.0)

3 (20.0)

3 (37.5)

4 (50.0)

1 (12.5)

3 (42.9)

2 (28.6)

0.9699

*At least 50% of the patients did not have the dose reduction. **Only 56 patients were treated with two or more cycles.

CUAJ • March-April 2016 • Volume 10, Issues 3-4

cꢀꢁꢀdꢂꢀꢁ eaP foꢃ ꢄꢀbꢀzꢂtꢀxꢅꢆ

Janssen, and Sanoﬁ; and has received honoraria from Sanoﬁ, as well as research funding from

Janssen. Dr. Aucoin has been an Advisory Board member for Sanoﬁ. Dr. Czaykowski has received

honoraria from Sanoﬁ. Dr. Sridhar has been an Advisory Board member for Astellas, Janssen, and

Sanoﬁ; and has received research funding from Sanoﬁ. Mrs. Alloul and Mr. Stewart are full-time

employees of Sanoﬁ-aventis Canada Inc. The remaining authors declare no competing ﬁnancial or

personal interests.

17. Bahl A, Masson S, Malik Z, et al. Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC):

Final quality-of-life (QoL) results with safety data from the United Kingdom (UK) Early Access Programme

(

EAP) (NCT01254279). BJU Int 2015;116:880-7. http://dx.doi.org/10.1111/bju.13069*

8. Wissing MD, van Oort IM, Gerritsen WR, et al. Cabazitaxel in patients with metastatic castration-resistant

prostate cancer: Results of a compassionate use program in the Netherlands. Clin Genitourin Cancer

013;11:238-50.

9. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemo-

therapy. N Engl J Med 2013;368:138-48. http://dx.doi.org/10.1056/NEJMoa1209096

0. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemother-

apy. N Engl J Med 2014;371:424-33. http://dx.doi.org/10.1056/NEJMoa1405095

1. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant pros-

tate cancer: Final overall survival analysis of the COU-AA-301 randomized, double-blind, placebo-controlled

phase 3 study. Lancet Oncol 2012;13:983-92. http://dx.doi.org/10.1016/S1470-2045(12)70379-0

2. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemother-

apy. N Engl J Med 2012;367(13):1187-97. http://dx.doi.org/10.1056/NEJMoa1207506

3. Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic

castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol

Acknowledgements: François Leblond and Pasha Javadi provided assistance with medical writing.

Previous publication: These results were presented in part as a poster at the 2014 ASCO Annual

Meeting (Saad et al. J Clin Oncol 2014;32:5:abstr 5062).

013;24:1807-12. http://dx.doi.org/10.1093/annonc/mdt136

This paper has been peer-reviewed.

4. Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity of enzalutamide (MDV3100) in patients

with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur

J Cancer 2014;50:78-84. http://dx.doi.org/10.1016/j.ejca.2013.08.020

References

25. Noonan KL, North S, Bitting RL, et al. Clinical activity of abiraterone acetate in patients with metastatic

castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013;24:1802-7. http://

dx.doi.org/10.1093/annonc/mdt138

26. Schrader AJ, Boegemann M, Ohlmann C, et al. Enzalutamide in castration-resistant prostate cancer patients

progressing after docetaxel and abiraterone. Eur Urol 2014;65:30-6. http://dx.doi.org/10.1016/j.

eururo.2013.06.042

27. Cheng HH, Gulati R, Azad A, et al. Activity of enzalutamide in men with metastatic castration-resistant

prostate cancer is affected by prior treatment with abiraterone and/or docetaxel. Prostate Cancer Prostatic

Dis 2015;18:122-7. http://dx.doi.org/10.1038/pcan.2014.53

28. Stevenson R, Fackrell DG, Ford D, et al. The sequential use of abiraterone and enzalutamide in metastatic

castrate resistant prostate cancer patients: Experience from seven U.K. centres. J Clin Oncol 2014;32:125.

29. Scholz MC, Lam RY, Turner JS, et al. Enzalutamide in men with prostate cancer resistant to docetaxel

and abiraterone. J Clin Oncol 2014;32:247

Sun Y, Niu J, Huang J. Neuroendocrine differentiation in prostate cancer. Am J Transl Res 2009; 1:148-62.

Tombal B. What is the pathophysiology of a hormone-resistant prostate tumour? Eur J Cancer 2011;

7:S179-88. http://dx.doi.org/10.1016/S0959-8049(11)70163-0

Zong Y, Goldstein AS. Adaptation or selection—mechanisms of castration-resistant prostate cancer. Nat

Rev Urol 2013;10:90-8. http://dx.doi.org/10.1038/nrurol.2012.237

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone

for advanced prostate cancer. N Engl J Med 2004;351:1502-12. http://dx.doi.org/10.1056/

NEJMoa040720

Bishr M, Saad F. Overview of the latest treatments for castration-resistant prostate cancer. Nat Rev Urol

013;10:522-8. http://dx.doi.org/10.1038/nrurol.2013.137

Malik Z, Payne H, Ansari J, et al. Evolution of the treatment paradigm for patients with metastatic

castration-resistant prostate cancer. Adv Ther 2013;30:1041-66. http://dx.doi.org/10.1007/s12325-

30. Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide

(MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel

and abiraterone treatment. Cancer 2014;120:968-75. http://dx.doi.org/10.1002/cncr.28518

31. Thomsen FB, Roder MA, Rathenborg P, et al. Enzalutamide treatment in patients with metastatic cas-

tration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate. Scand J Urol

2014;48:268-75. http://dx.doi.org/10.3109/21681805.2013.860189

32. Roeder MA, Thomsen FB, Brasso K, et al. Biochemical response to enzalutamide therapy in patients with

mCRPC following docetaxel and abiraterone treatment. J Clin Oncol 2014;32:202.

33. Thomson D, Charnly N, Parikh O. Enzalutamide after failure of docetaxel and abiraterone in metastatic

castrate resistant prostate cancer (mCRPC): Results from an expanded access program. J Clin Oncol

2014;32:188.

13-0070-z

Rathkopf D, Scheer HI. Androgen receptor antagonists in castration-resistant prostate cancer. Cancer J

013;19:43-9. http://dx.doi.org/10.1097/PPO.0b013e318282635a

Vrignaud P, Sémiond D, Lejeune P, et al. Preclinical antitumor activity of cabazitaxel, a semisyn -

thetic taxane active in taxane-resistant tumours. Clin Cancer Res 2013;19:2973-83. http://dx.doi.

org/10.1158/1078-0432.CCR-12-3146

de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic

castration-resistant prostate cancer progressing after docetaxel treatment: A randomized open-label trial.

Lancet 2010;376:1147-54. http://dx.doi.org/10.1016/S0140-6736(10)61389-X

0. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive

prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical

Trials Working Group. J Clin Oncol 2008;26:1148-59. http://dx.doi.org/10.1200/JCO.2007.12.4487

1. Heidenreich A, Scholz H-J, Rogenhofer S, et al. Cabazitaxel plus prednisone for metastatic castration-

resistant prostate cancer progressing after docetaxel: Results from the German compassionate-use program.

Eur Urol 2013;63:977-82. http://dx.doi.org/10.1016/j.eururo.2012.08.058

2. Al Nakouzi N, Le Moulec S, Albigès L, et al. Cabazitaxel remains active in patients progressing after

docetaxel followed by novel androgen receptor pathway-targeted therapies. Eur Urol 2015;68(2):228-35.

http://dx.doi.org/10.1016/j.eururo.2014.04.015

34. Sandhu GS, Parikh RA, Appleman LJ, et al. Enzalutamide after abiraterone in patients with metastatic

castrate-resistant prostate cancer (mCRPC). J Clin Oncol 2014;32:240.

35. Schnadig ID, Bhor M, Vogelzang NJ, et al. Sequencing of cabazitaxel and abiraterone acetate following

docetaxel in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2013;31:79.

36. Zhu ML, Horbinski CM, Garzotto M, et al. Tubulin-targeting chemotherapy impairs androgen receptor activity in

prostate cancer. Cancer Res 2010;70:7992-8002. http://dx.doi.org/10.1158/0008-5472.CAN-10-0585

37. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe:

Estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-403. http://dx.doi.org/10.1016/j.

ejca.2012.12.027

3. Pezaro CJ, Omlin AG, Altavilla A, et al. Activity of cabazitaxel in castration-resistant prostate cancer

progressing after docetaxel and next-generation endocrine agents. Eur Urol 2014;66:459-65. http://

dx.doi.org/10.1016/j.eururo.2013.11.044

4. Bracarda S, Gernone A, Gasparro D, et al. Real-world cabazitaxel safety: The Italian early-access pro-

gram in metastatic castration-resistant prostate cancer. Future Oncol 2014;10:975-83. http://dx.doi.

org/10.2217/fon.13.256

38. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9-29. http://dx.doi.

org/10.3322/caac.21208

39. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2013.

Toronto, ON: Canadian Cancer Society; 2013. http://www.cancer.ca/en/cancer-information/can-

cer-101/canadian-cancer-statistics-publication/?region=on. Accessed February 25, 2016.

40. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.http://

dx.doi.org/10.3322/caac.20107

5. Heidenreich A, Bracarda S, Mason M, et al. Safety of cabazitaxel in senior adults with metastatic

castration-resistant prostate cancer: Results of the European compassionate-use programme. Eur J Cancer

014;50:1090-9. http://dx.doi.org/10.1016/j.ejca.2014.01.006

6. Houede N, Eymard J, Zoubier T. Safety data of cabazitaxel (Jevtana) in patients treated for metastatic

castration resistant prostate cancer after docetaxel treatment: Result of a cohort of patients during the

temporary authorization for use in France (ATU). Ann Oncol 2012;23:ix314-5.

Correspondence: Dr. Fred Saad, Université de Montréal Hospital Centre, CRCHUM, Montreal, QC,

Canada; fred.saad@umontreal.ca

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