Page 5 - Metastatic castration-naive and castration-sensitive prostate cancer: CUA/CUOG

guideline: mCnPC & mCSPC

(5 mg) plus ADT or ADT alone; 52% of the patients had meta- arm and no survival differences were observed between the
static disease, 20% had node-positive or node-indeterminate two arms. Prior docetaxel of up to six cycles was allowed,
non-metastatic disease, and 28% had node-negative, non- and 18% (205) men received at least one dose of docetax-
metastatic disease; 95% had newly diagnosed disease. In a el prior to randomization; subgroup analysis showed that
subgroup analysis, the OS benefit was seen in PC patients rPFS benefit was seen in both chemotherapy-treated and
with metastatic disease (HR 0.61; 95% CI 0.49–0.75) but chemotherapy-naive patients. As well, although 35% (405
not those with non-metastatic, high-risk patients (HR 0.75; patients) of men were low-volume based on CHAARTED
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95% CI 0.48–1.18). The impact of volume tumor burden criteria, benefit in rPFS with enzalutamide-treated patients
was not reported. was seen regardless of volume of disease.
In a recent, unplanned, post-hoc analysis of 759 evalu- ENZAMET was an open-label clinical trial that randomized
able patients with bone metastases in the above STAMPEDE 1125men with mCNPC/mCSPC to receive ADT and enzaluta-
trial, patients were reclassified using CHAARTED “high- or mide daily (160 mg) or a non-steroidal antiandrogen (NSAA:
low-volume” criterion or LATITUDE “high- or low-risk” cri- bicalutamide, nilutamide, or flutamide), with a primary end-
terion. Men with mCNPC had OS benefit with the addition point of OS. There was an OS benefit in the enzalutamide plus
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of abiraterone acetate and prednisone to ADT irrespective of ADT arm compared to NSAA (HR 0.67; 95% CI 0.52–0.86;
risk stratification for “risk” or “volume.” Using CHAARTED p=0.002). Kaplan-Meier estimates of OS at three years were
criteria, low-volume HR was 0.66 (95% CI 0.44–0.98) and 80% in the enzalutamide group and 72% in the NSAA arm.
high-volume HR was 0.54 (95% CI 0.41–0.70); using the Unlike ARCHES, concurrent use of docetaxel was allowed and
LATITUDE criteria, low-risk HR was 0.64 (95% CI 0.42–0.97) the decision to treat with chemotherapy was at the discretion
and high-risk HR was 0.60 (95% CI 0.46–0.78). Although of the investigator. Use of chemotherapy was well-balanced
these results are intriguing, the retrospective nature of the between the two arms (45% of those receiving enzalutamide
reclassification of risk and tumor volume is a significant and 44% of those receiving a NSAA planned for early docetax-
limitation and, thus, the results can only be considered el use). In a subgroup analysis, the benefits of enzalutamide on
hypothesis-generating. OS appeared only in the group without planned early docetax-
el use (concurrent docetaxel: HR 0.9; 95% CI 0.62–1.31; no
Enzalutamide (160 mg/day) is a treatment option for concurrent docetaxel: HR 0.8; 95% CI 0.59–1.07). Although
mCNPC/mCSPC regardless of volume of disease (Level of the authors state that the study is underpowered and data
evidence 1, Strong recommendation). is too immature to specifically answer whether combination
docetaxel and enzalutamide is beneficial in mCNPC/mCSPC,
Enzalutamide should not be used in combination (con- these results demonstrate that this combination should not be
current use) with docetaxel to treat mCNPC/mCSPC (Level used until further evidence is shown for its benefits.
of evidence 2, Strong recommendation).
Apalutamide (240 mg) is a treatment option for men with
Enzalutamide may be considered in mCSPC patients pre- mCNPC/mCSPC regardless of volume of disease (Level of
viously treated with docetaxel chemotherapy (sequential evidence 1, Strong recommendation).
use) (Level of evidence 1, Weak recommendation).
Apalutamide inhibits the AR by preventing its nuclear
Enzalutamide binds to the androgen receptor (AR) and translocation and DNA binding. The first large, randomized
inhibits the AR nuclear translocation and interaction with clinical trial assessing apalutamide in mCNPC/mCSPC was
DNA. Suppression of the AR with enzalutamide was initially the TITAN trial, which randomized 1052 men with mCNPC/
shown to improve survival in docetaxel-naive or treated mCSPC (any) to receive apalutamide (240 mg once daily)
mCRPC. 31,32 Two recent studies assessed the role of enzalu- plus ADT or ADT alone. As well, 10.7% received previous
tamide in mCNPC: ARCHES and ENZAMET. 33,34 docetaxel therapy and 37.3% had low-volume disease. With
The ARCHES trial randomized 1150 mCNPC/mCSPC a median of 22.7 months of followup, rPFS at 24 months was
patients to either enzalutamide (160 mg/day) plus ADT or 68.2% in the apalutamide group and 47.5% in the placebo
placebo plus ADT. The primary endpoint was radiological group (HR 0.48; 95% CI 0.39–0.60; p<0.001). Benefit with
progression-free survival (rPFS), defined as the time from apalutamide in rPFS was seen regardless of prior chemo-
randomization to the first objective evidence of radiographic therapy use or disease burden. OS at 24 months was also
disease progression or death. The combination of enzaluta- greater with apalutamide than with placebo (82.4% in the
mide plus ADT improved rPFS compared to placebo-ADT apalutamide group vs. 73.5% in the placebo group; HR 0.67;
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(HR 0.39; 95% CI 0.30–0.50; p= 0.001; median not reached 95% CI 0.51–0.89; p=0.005). Benefit with apalutamide in
vs. 19.0 months). Due to the immaturity of the study and the OS was seen regardless of disease burden.
median duration of OS, median OS was not reached in either

CUAJ • February 2020 • Volume 14, Issue 2 21