Introduction
Androgen deprivation therapy (ADT) alone or in combination
with chemotherapy is usually the initial treatment
of metastatic castration-sensitive prostate cancer.
This treatment creates an objective tumor response in
most patients and alleviates symptoms.[] However,
progression is inevitable in these patients and additional
treatments are required. The disease is called castration-resistant prostate cancer (CRPC) after developing
resistance to ADT. Expected survival rate is low at this
level of the disease and patients die substantially due
to CRPC.[,] Therefore, various agents have been used
to treat CRPC. Docetaxel is the first agent used following
ADT in this regard. In a study, docetaxel provided
overall survival (OS) in patients compared to mitoxantrone.[] Other agents were used alone or in combination
after above-mentioned success of docetaxel, but treatthey
were not effective.[-] Cabazitaxel was found to
be effective in patients with CRPC just like docetaxel;
however, it was used in post-docetaxel period as it was
identified that there was no difference between cabazitaxel
and docetaxel in a head-to-head study.[]
Agents affecting the androgen pathway were also
used in CRPC patients. Abiraterone which is an androgen
synthesis inhibitor and enzalutamide which is an
androgen receptor blocker were used in chemotherapy-
naive CRPC patients. Abiraterone was superior to
placebo in a study comparing abiraterone with placebo
and contributed to both progression-free survival and
OS.[-] Similarly, enzalutamide was compared
with placebo in chemotherapy-naive CRPC patients
and it also contributed to progression-free survival and
OS.[-]
After developing castration resistance, patients
have limited response to various treatments; therefore,
treatments focused on castration-sensitive period.
Chemotherapy and agents active in the androgen
pathway are frequently used in combination with ADT
in this period. Treatments combined with ADT have
become the standard, especially in patients with high
disease burden and high risk. However, ADT alone
is frequently administered as the initial treatment in
metastatic patients. There is no exact information
about which treatment should be chosen in these patients
after developing castration resistance.
In this study, we aim to determine which treatment
is more appropriate in castration-resistant chemotherapy-
naive patients. Therefore, docetaxel and agents
active in the androgen pathway (abiraterone and enzalutamide)
were compared retrospectively in patients
progressing on ADT.
Methods
The study was designed as a retrospective and multicenter
study. Patients from five centers in Turkey were
included in the study. Files of the patients who applied
to these centers between 2016 and 2020 were analyzed
and the data were obtained. Inclusion criteria
were age >18 years, having metastatic disease, being
local treatment naive (surgery or radiotherapy), being
chemotherapy naive, and progressing only on ADT.
The patients were divided into two groups based on
the treatments they received. The first group included
those patients who received docetaxel (chemotherapy
group). The second group included the patients
who received enzalutamide or abiraterone (hormonal
therapy group).
OS was defined as the time from the start of second
line therapy to death or the last follow-up examination.
Progression-free survival was defined as the time
from the start of second-line therapy to the date of
progression, death, or the last follow-up examination.
Tumor progression was evaluated according to the
RECIST criteria (only PSA elevation was not accepted
as progressive disease). Moreover, following parameters
which may affect the survival of the patients were
analyzed in Cox regression model: Age (over 65 vs.
under 65), location of metastasis (bone only vs. others),
Gleason score (9-10 vs. ≤8), and disease burden
(high volume vs. low volume-CHAARTED definition).
The study was approved by the Manisa Celal
Bayar University Faculty of Medicine Ethics Committee
(No: 20.478.486, Date: 23/12/2020).
All analyses were performed using the SPSS statistical
software program package (SPSS version 20.0
for Windows). The Chi-square test analyzed the differences
in the clinical characteristics between the
two groups. OS was calculated with the log-rank test.
The Kaplan-Meier method was used to draw survival
curves. The Cox proportional hazards regression
model was used to determine statistically significant
variables related to OS. Differences were assumed to
be significant when p<0.05 was considered.
Results
A total of 80 patients were included in the study. A
total of 44 patients received docetaxel and 36 patients
received hormonal therapy (abiraterone or enzalutamide).
The mean age of patients in the chemotherapy
group was 65.5 years (43-82), and it was 71.5 years in
the hormonal therapy group (48-96). The mean followup
duration was 20.4 months for chemotherapy group
and 15.6 months for hormonal therapy group. When
the distribution rates of age, location of metastasis,
Gleason score, and disease burden parameters in the
groups were analyzed, it was found that only patients
over 65 years of age were statistically higher in the hormonal
treatment group. The characteristics of the patients
are shown in Table 1.
Table 1: General characteristics of patients
The effect of these four variables (age, location of
metastasis, Gleason score, and disease burden) on the
survival of all patients was also studied in in the multivariate
analysis. Among these variables, only the Gleason
score had a statistically significant effect on the
survival (p=0.029) (Table 2).
Table 2: Cox regression
Median OS of the chemotherapy group was 18.66
months, it was 16.26 months in the hormonal treatment group. There was no statistically significant difference
between the groups (p=0.311). OS data are
shown in Figure 1. A total of 15 patients in the chemotherapy
group and 11 patients in the hormonal treatment
group were alive at the time of data entry.
Fig 1: Overall survival of patients.
Median progression-free survival of the chemotherapy
group was 5.6 months, while it was 9 months
in the hormonal therapy group. There was statistically
significant difference between the groups (p=0.024).
Progression-free survival data are shown in Figure 2.
Nine patients in the hormonal therapy group and three
patients in the chemotherapy group were still on their
treatment at the time of data entry.
Fig 2: Progression free survival of patients.
PFS: Progression free survival.
Discussion
It is not clear which agent should be used in the treatment
of metastatic castration-resistant chemotherapynaive
patients. Many options have been evaluated until
today; docetaxel has become prominent as treatment
of choice for chemotherapy, while abiraterone and enzalutamide have become the hormonal treatments of
choice. There is no prospective study on these agents;
therefore, the treatment of these patients is up to the
clinicians" decision.
When we examined the studies of these agents in
CRPC patients, in a Phase 3 randomized study, where
docetaxel, which was the first agent used, was compared with mitoxantrone, median survival in patients
who received docetaxel was found to be 18.9 months.
[] In a study on abiraterone in this population, median
survival was 34.7 months.[] In another study on
enzalutamide in CRPC patients, OS was found to be
35.3 months.[]
In the present study, the OS of docetaxel was 18.66
months, and it was 16.26 months for abiraterone and
enzalutamide which are hormonal therapies. In the
numerical analysis of the results, the survival of the
patients in the docetaxel arm was almost the same as
the pivotal study.[] However, this was not the case for
the patients taking enzalutamide and abiraterone. The
OS of these agents with an OS of 34 months in their
pivotal study was 16.26 months in the present study.
This may be due to the difference in the selection of
patients. In pivotal studies of these agents, asymptomatic
patients were especially included. As there were
no such selection criteria in our study, it may have resulted
in the difference. In Turkey, where the present
study was conducted, abiraterone or enzalutamide can
be used in patients who are not suitable for chemotherapy.
Therefore, patients whose general condition
is relatively worse receive hormonal therapies. The
age parameter was significantly in favor of hormonal
therapies and this result also promotes the condition.
OS may be low in our study due to this disadvantage
in patient selection. Poor survival in the pivotal study
of docetaxel may result from not using other agents,
which prolong life time, in sequential therapy.
In our study, progression-free survival was statistically
significantly higher in the hormonal therapy
arm than the group receiving chemotherapy. Despite
the above-mentioned disadvantage in the selection of
the patients, hormonal therapies were successful in
progression-free survival compared to chemotherapy;
however, the difference did not reflect on OS. This success
in progression-free survival, on the other hand, obtained
despite the limited number of patients. Therefore,
based on the results of our study, hormonal therapies
(abiraterone or enzalutamide) are more successful than
docetaxel in castration-resistant metastatic chemotherapy-
naive patients. Nevertheless, it is not possible to
reach a definite conclusion based on the results of our
retrospective study and larger prospective randomized
controlled studies are needed on this subject.
Conclusion
There is no consensus on which drugs should be administered
in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. There
was a statistical difference in progression-free survival
in favor of hormonal therapies in our study. The difference
did not reflect on OS and there was no difference
between hormonal therapies and docetaxel. Heterogeneity
in the selection of patients is considered to lead
to this result; however, larger randomized controlled
studies are needed to determine the most appropriate
treatment in these patients.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the Manisa Celal Bayar University Faculty of Medicine Ethics
Committee (No: 20.478.486, Date: 23/12/2020).
Financial Support: None declared.
Authorship contributions: Concept - S.Y.; Design - A.P.E.;
Supervision - A.P.E.; Funding - None; Materials - A.P.E.;
Data collection and/or processing - S.Y.; Data analysis and/
or interpretation - S.Y.; Literature search - S.Y.; Writing -
S.Y.; Critical review - S.Y.
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