Keywords abiraterone - androgen deprivation therapy - prostate cancer - prostate-specific antigen
- real-world study
Introduction
Prostate cancer stands as the second most frequently diagnosed cancer in men and ranks
fifth among the leading causes of cancer-related deaths worldwide.[1 ] It is anticipated that the global burden of prostate cancer will escalate to 1.7
million new cases and 499,000 fatalities per year by 2030.[2 ] As per the GLOBOCAN 2020 estimates, prostate cancer contributed to 2.1% of cancer-related
mortalities in Asia in the year 2020.[3 ] Within Thailand, prostate cancer occupies the eighth position in terms of cancer-related
mortality with 3,837 deaths per year.[3 ]
[4 ] The escalating incidence of prostate cancer is postulated to be a consequence of
enhanced longevity and the assimilation of Westernized lifestyle practices, catalyzed
by socioeconomic advancements.[5 ] The mortality-to-incidence ratio for prostate carcinoma within Thailand is notably
documented at 0.51, a contrast to the 0.09 metric observed in more medically advanced
regions such as the United States. This differential in survival indices for prostate
carcinoma in the Thai context may be partially attributed to the suboptimal utilization
of prostate-specific antigen (PSA) diagnostic screening, relative to other nations.[6 ] The European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate,
Lung, Colorectal, and Ovarian (PLCO) trials present compelling evidence supporting
the capacity of PSA screening to mitigate prostate cancer-specific mortality.[7 ]
Androgen deprivation therapy (ADT) has been a mainstay treatment for prostate cancer,
attributed to cancer cells' dependence on androgens for growth and progression. ADT
has the potential to induce tumor regression and alleviate symptoms in metastatic
prostate cancer patients. However, a significant proportion eventually acquire resistance
to initial ADT due to a range of mechanisms, leading to a condition recognized as
castration-resistant prostate cancer (CRPC).[8 ]
The understanding of resistance mechanisms in metastatic CRPC (mCRPC) has spurred
the development of novel drugs aimed at treating mCRPC. The treatment landscape for
mCRPC has rapidly transformed with the introduction of new therapies. The U.S. Food
and Drug Administration (FDA) has approved several agents for managing mCRPC, including
docetaxel, sipuleucel-T, abiraterone acetate, enzalutamide, cabazitaxel, radium-223,
olaparib, etc.[9 ]
Abiraterone acetate, an active prodrug precursor to abiraterone, functions as a potent
and specific inhibitor of the enzyme CYP17A1, pivotal in the androgenic biosynthetic
cascade.[10 ] The National Comprehensive Cancer Network (NCCN) guidelines advocate for the utilization
of abiraterone acetate in treating CRPC as a category 1 recommendation, either before
or after docetaxel therapy.[11 ] Abiraterone acetate has demonstrated its ability to prolong survival in patients
with mCRPC, initially in the mCRPC setting and subsequently in high-risk, high-volume
de novo metastatic hormone-sensitive prostate cancer (mHSPC). Recommended dose of
abiraterone for mCRPC is 1,000 mg orally once daily with prednisone 5 mg orally twice
daily, and for mHSPC is 1,000 mg orally once daily with prednisone 5 mg orally once
daily. Dose modification is required for patients with baseline moderate hepatic impairment
and for patients who develop hepatotoxicity during treatment.[12 ]
[13 ] A randomized clinical trial compared low-dose abiraterone (250 mg after a low-fat
meal) to a standard dose (1,000 mg, fasting) in men with mCRPC. Although noninferiority
could not be established with statistical rigor because of the low power of the trial,
it was supported strongly by the PSA data and by similar Pharmacodynamic (PD) effects
of the low and standard doses.[14 ] The NCCN added low-dose abiraterone with food as an acceptable alternative to the
standard dose for treatment of men with prostate cancer in resource-constrained countries.[11 ]
This real-world, retrospective observational study was undertaken to assess the safety
and efficacy of abiraterone in patients with metastatic prostate cancer treated with
Abiratred in routine clinical practice in Thailand.
Materials and Methods
This single-center, retrospective, real-world observational clinical study compiled
data from prostate cancer patients treated at Siriraj Hospital between June 2018 and
April 2022. Ethical approval was granted by the Siriraj Institutional Review Board.
A total of 47 patients who had received generic abiraterone (Abiratred) treatment
were screened, including those with mCRPC (asymptomatic or mildly symptomatic) following
failed ADT, those not yet exposed to chemotherapy, those newly diagnosed with high-risk
mHSPC, or those mHSPC patients who had progressed after a docetaxel-based regimen.
Complete data were accessible for 35 patients, all above 18 years old, and nonparticipants
in other clinical trials. Information encompassing demographics, medical history,
general examination, vital signs, comorbidities, health status, and prostate cancer-related
details was gathered. Analysis involved patients with a follow-up duration of at least
6 months, concentrating on primary and secondary outcomes.
The study's primary outcome was the PSA response rate (≥ 50% decline in PSA level
from baseline). Secondary outcomes included defining PSA progression-free survival
(PFS) as the duration from treatment initiation until PSA progression (defined as
an increase of 25% or more and an absolute increase of 2 ng/mL or more from the nadir).
Additionally, disease control rate (DCR) was assessed, representing the percentage
of patients with advanced or metastatic cancer who achieved complete response, partial
response, or stable disease. The study also evaluated the abiraterone's safety by
documenting all adverse events occurring throughout the study period, providing a
detailed description of each event.
Statistical Analysis
The statistical analysis conducted on the gathered data primarily involved descriptive
statistics. Demographic and baseline characteristics of the patient population were
elucidated using absolute and relative frequencies for categorical variables, and
measures of central tendency (mean, standard deviation) and dispersion (minimum and
maximum) for continuous variables. Likewise, summary statistics for the study outcomes
were presented utilizing absolute and relative frequencies for categorical variables,
and measures of central tendency and dispersion for continuous variables. All statistical
analyses were carried out using STATA V 15.0 software.
Results
The study included a population of patients presenting varying stages of advanced
or metastatic prostate cancer. Most (82.9%) of the patients had mCRPC with ADT failure
and were chemotherapy naive. The remaining patients were newly diagnosed with high-risk
mHSPC (14.3%) or had mCRPC that had progressed post a docetaxel-based chemotherapy
regimen (2.9%). The entire study group consisted of 35 male patients, with a median
age of 73 years (range: 53–85 years). Each patient received abiraterone monotherapy
at different dosage regimens: 77.1% received 1,000 mg once daily, 11.4% received 750 mg
once daily, 5.7% received 500 mg once daily, and 5.7% received 250 mg once daily with
a low-fat meal. At the commencement of abiraterone treatment, the median PSA level
was 11.6 ng/mL. Demographic particulars, baseline characteristics, and imaging assessment
findings are detailed in [Table 1 ].
Table 1
Summary statistics of demographics
Parameter
Overall (N = 35)
Age (y)
N
35
Median (range)
73.00 (53–85)
Height (cm)
N
35
Mean (SD)
168.02 (5.73)
Weight (kg)
N
34
Mean (SD)
67.85 (11.23)
BMI (kg/m2 )
N
34
Median (range)
24.47 (13.3–35.2)
Systolic blood pressure (mm Hg)
N
34
Mean (SD)
135.64 (15.48)
Diastolic blood pressure (mm Hg)
N
34
Mean (SD)
76.94 (11.38)
Oral body temperature (°C)
N
34
Mean (SD)
36.48 (0.24)
Pulse rate (beats per minute)
N
34
Mean (SD)
79.97 (22.13)
Respiratory rate (breaths per minute)
N
34
Mean (SD)
16.52
Aspartate aminotransferase (AST)
N
34
Mean (SD)
30.5 (16.74)
Alanine aminotransferase (ALT)
N
34
Median (range)
21.5 (8–108)
Bilirubin
N
34
Mean (SD)
0.54 (0.32)
Sodium
N
32
Mean (SD)
138.62 (3.05)
Potassium
N
32
Mean (SD)
4.33 (0.48)
Calcium
N
8
Mean (SD)
9.5 (0.64)
Serum creatinine
N
33
Median (range)
1.03 (0.66–1.73)
Primary diagnosis of prostate cancer, n (%)
A: Newly diagnosed high-risk metastatic hormone-sensitive prostate cancer
5 (14.28%)
B: Metastatic castration-resistant prostate cancer (asymptomatic or mildly symptomatic)
in whom androgen deprivation therapy has failed and chemotherapy was not initiated
29 (82.85%)
C: Metastatic castration-resistant prostate cancer in whom disease has progressed
on or after a docetaxel-based chemotherapy regimen
1 (2.85%)
Details pertaining to dosage regimen of abiraterone, n (%)
Abiraterone 250 mg once daily
2 (5.71%)
Abiraterone 500 mg once daily
2 (5.71%)
Abiraterone 750 mg once daily
4 (11.42%)
Abiraterone 1,000 mg once daily
27 (77.14%)
Prostate-specific antigen (PSA) level at time of abiraterone treatment initiation
N
35
Median (range)
11.6 (0.003–1633.00)
Whole body radionuclide scan, n (%)
Yes
18 (51.42%)
If yes, then
Bone metastasis
10 (55.56%)
Multiple bone metastasis
7 (38.89%)
No evidence of bone metastasis
1 (5.56%)
CT/MRI assessment, n (%)
N
26
Yes
23 (88.46%)
If yes, then
Bone metastasis
5 (21.73%)
Multiple bone metastasis
4 (17.39%)
Multiple lymph nodes
8 (34.78%)
No liver and lung metastasis
5 (21.73%)
Recurrence tumor
1 (4.34%)
Abbreviations: BMI, body mass index; CT, computed tomography; MRI, magnetic re4sonance
imaging; SD, standard deviation.
Primary Outcomes
The study's primary endpoint was the PSA response rate (≥ 50% decline in PSA level
from baseline). Among the 35 patients included in the study, 23 (65.7%) achieved this
response ([Fig. 1 ]).
Fig. 1 Waterfall plot of percent change in prostate-specific antigen (PSA) level from baseline
to last evaluation. Note: Values of PSA percentage changes for 3 patients were outliers
and were not included in the graph above.
Secondary Outcomes
The PSA PFS rate at 6 months stood at 65.6% (21/32). Another secondary outcome measured
was the patient's best response to therapy, as evaluated by the DCR. It was determined
that 71.4% (25/35) of patients experienced disease control, with 54.3% (19/35) exhibiting
stable disease and 17.1% (6/35) encountering a partial response. The outcomes of efficacy
measures are concisely presented in [Table 2 ]. [Fig. 1 ] provides a waterfall plot illustrating the percent change in PSA level from baseline
to the last evaluation.
Table 2
Summary statistics of patients who achieved PSA response (≥ 50% decline in PSA level
from baseline) and patient's best response estimate at the last visit to the hospital
Parameter
Overall (N = 35)
PSA response rate (≥ 50% decline in PSA level from baseline), n (%)
No
12 (34.29%)
Yes
23 (65.71%)
Patient's best response to treatment, n (%)
Complete response (CR)
0 (0.00%)
Partial response (PR)
6 (17.14%)
Stable disease (SD)
19 (54.28%)
Disease control rate (CR + PR + SD)
25 (71.42%)
Progressive disease
10 (28.57%)
Prostate-specific antigen (PSA) progression-free survival (PFS) (defined as the date
that an increase of 25% or more and absolute increase of 2 ng/mL or more from the
nadir), n (%), follow-up after 6 months (N = 32)
No
11 (34.37%)
Yes
21 (65.62%)
Abbreviation: PSA, prostate-specific antigen.
Overall, the administration of abiraterone was determined to be safe and well-tolerated,
with 85.7% (30/35) of patients experiencing no serious adverse events. Among the remaining
14.3% (5/35) of patients, the reported serious adverse events included Escherichia coli septicemia, herpes simplex virus infection, urinary tract infection with septic shock,
hypertensive urgency, and fracture of the right femur ([Table 3 ]). None of these adverse events were deemed likely to be related to abiraterone.
No abiraterone-related deaths were observed in this study.
Table 3
Summary statistics of adverse events
Parameter
Overall (N = 35)
Adverse events, n (%)
Yes
5 (14.28%)
No
30 (85.71%)
Serious adverse events, n (%)
Fracture of right femur
1 (2.86%)
Escherichia coli septicemia
1 (2.86%)
Herpes simplex infection
1 (2.86%)
Urinary tract infection with septic shock
1 (2.86%)
Hypertensive urgency
1 (2.86%)
[Table 4 ] provides a concise overview of patient responses to different dosages of abiraterone
treatment, focusing on PSA response rates and disease control. Among the various dosage
groups, patients receiving the 1,000 mg daily regimen demonstrated the highest PSA
response rate of 59.25%, while the overall PSA response rate was 65.71%. DCR, including
complete responses, partial responses, and stable diseases, was achieved in 71.42%
of cases. However, 28.57% of patients experienced progressive disease.
Table 4
Summary statistics of patients who achieved PSA response (≥ 50% decline in PSA level
from baseline) and patient's best response estimate at the last visit to the hospital
for each dosage regimen of abiraterone
Parameter
Overall (N = 35)
Abiraterone 250 mg once daily (N = 2)
Abiraterone 500 mg once daily (N = 2)
Abiraterone 750 mg once daily (N = 4)
Abiraterone 1,000 mg once daily (N = 27)
PSA response rate (≥ 50% decline in PSA level from baseline), n (%)
No
12 (34.29%)
0 (00.00%)
0 (00.00%)
1 (25.00%)
11 (40.74%)
Yes
23 (65.71%)
2 (100.00%)
2 (100.00%)
3 (75.00%)
16 (59.25%)
Patient's best response estimate to abiraterone treatment, n (%)
Complete response (CR)
0 (0.00%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
Partial response (PR)
6 (17.14%)
0 (0.00%)
0 (0.00%)
1 (25.00%)
5 (18.51%)
Stable disease (SD)
19 (54.28%)
2 (100.00%)
2 (100.00%)
3 (74.00%)
12 (44.44%)
Disease control rate (CR + PR + SD)
25 (71.42%)
2 (100.00%)
2 (100.00%)
4 (100.00%)
17 (62.96%)
Progressive disease
10 (28.57%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
10 (37.03%)
Prostate-specific antigen (PSA) progression-free survival (PFS) (defined as the date
that an increase of 25% or more and absolute increase of 2 ng/mL or more from the
nadir), n (%), follow-up after 6 months (N = 32)
No
11 (34.37%)
0 (0.00%)
2 (100.00%)
3 (75.00%)
6 (25.00%)
Yes
21 (65.62%)
2 (100.00%)
0 (0.00%)
1 (25.00%)
18 (75.00%)
Abbreviation: PSA, prostate-specific antigen.
Discussion
This real-world clinical study showcased the efficacy of abiraterone acetate, an inhibitor
of androgen biosynthesis, among patients with advanced/metastatic prostate cancer.
The primary endpoint, involving a reduction in PSA serum levels from baseline, coupled
with favorable prespecified secondary outcomes, substantiates the antitumor activity
of abiraterone.
In the COU-AA-302 phase III trial, abiraterone acetate (1,000 mg) along with prednisone
(5 mg twice daily) was compared with placebo plus prednisone in patients with mCRPC
who had not undergone prior chemotherapy. Abiraterone exhibited improvement in radiographic
PFS, overall survival, and delayed clinical deterioration and initiation of chemotherapy
in individuals with mCRPC.[15 ]
[16 ] Following these results, the U.S. FDA approved abiraterone acetate, indicating a
significant breakthrough and a major stride in treating patients with mCRPC.[17 ] The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for
the diagnosis, treatment, and follow-up of prostate cancer (2022) endorse abiraterone
(ESMO-MCBS v1.1 score 4) as a primary treatment choice for asymptomatic/mildly symptomatic
patients with chemotherapy-naive mCRPC (grade I, level A).[18 ] Similarly, the NCCN guidelines (2024) classify abiraterone as a category 1 preferred
treatment for patients with first-line mCRPC.[11 ]
In our study, 65.7% of the patients attained the primary endpoint of PSA response
rate (defined as a reduction of ≥ 50% in PSA levels). Previous research has likewise
documented rates of PSA response to abiraterone treatment in patients with mCRPC that
are comparable. In the COU-AA-302 trial, the PSA response rate was 62%.[15 ] In a recent real-world experience within the Southeast Asian cohort, the PSA response
rate with abiraterone was noted to be 58%.[19 ] Likewise, Facchini et al reported that a significant proportion of patients (56%)
exhibited a PSA response upon initiating abiraterone therapy.[20 ] Leibowitz-Amit et al identified a confirmed PSA response to abiraterone in 44 out
of 108 assessable mCRPC patients (41%, 95% confidence interval [CI]: 31–50%).[21 ]
Numerous studies have validated the clinically meaningful advantage presented by abiraterone
acetate in terms of the median PSA PFS within advanced/metastatic prostate cancer.
Koninckx et al reported a median time to PSA progression and PFS of 4.4 months (p = 0.003) and 5.1 months (p = 0.034), respectively, among patients who underwent abiraterone treatment prior
to chemotherapy.[22 ] Similarly, Raju et al observed that the PSA PFS was 5 months (95% CI: 3.3–6.7; p = 0.022) for individuals undergoing abiraterone treatment in the context of mCRPC.[23 ] In our study, the PSA PFS at 6 months demonstrated a rate of 65.6%.
The effectiveness of CRPC treatments on disease response are intricately linked to
patients' adherence to the prescribed dosage regimens. Research has demonstrated that
patients exhibit higher medication adherence and a reduced risk of dose reduction
when treated with abiraterone as compared to enzalutamide therapy.[24 ] During the Prostate Cancer Consensus Conference for Developing Countries, the recommended
best practice for mCRPC involves an abiraterone regimen of 1,000 mg along with prednisone
5 mg/d. However, in settings with limited resources, an acceptable alternative is
the utilization of abiraterone 250 mg accompanied by fatty foods and prednisone 5 mg/d.[25 ]
In clinical trials, abiraterone has exhibited a generally favorable safety profile,
yet potential adverse effects linked to its mechanism of action are possible. Many
studies have documented grade 1 to 2 adverse events associated with abiraterone, including
fluid retention, asthenia, elevated transaminases, and hypertension.[26 ] A meta-analysis conducted by Moreira et al indicated an increased risk of cardiovascular
events with abiraterone treatment.[27 ] Within our study, occurrences of adverse events such as E. coli septicemia, herpes simplex virus infection in the buttock region, urinary tract infection
with septic shock, hypertensive urgency, and closed fracture of the neck of the right
femur were observed. However, most of these incidents were not found to be directly
linked to abiraterone treatment. It is noteworthy that treatment with abiraterone
can induce mineralocorticoid-associated adverse events due to the reduction in glucocorticoid
production, thereby leading to an augmented production of adrenocorticotropic hormone
and mineralocorticoid excess. Consequently, this can contribute to the onset or exacerbation
of hypertension, hypokalemia, and fluid retention in certain patients.[28 ]
[29 ]
Bjartell et al conducted a prospective observational study using the Prostate Cancer
Registry, assessing mCRPC patients treated with abiraterone acetate plus prednisone
or prednisolone as first-line or post-docetaxel therapy. This study also examined
the efficacy parameters such as PSA response rate, PSA PFS, and DCR as those of our
study. Findings indicated abiraterone's efficacy within real-world settings, with
notable PSA responses and stable disease proportions. Comparable adverse event reporting
highlights abiraterone's safety profile. These results collectively underscore abiraterone's
effectiveness and safety, reinforcing its significance in mCRPC treatment. Both studies
observed a PSA response rate of 65.7%, with close alignment in PSA PFS (8.9 months
by Bjartell et al, 6 months in our study) and DCR (71.4% in both studies). This coherence
supports abiraterone's role as a valuable mCRPC treatment option.[30 ]
Cindolo et al also evaluated the safety and efficacy of abiraterone acetate in the
context of mCRPC within real-world settings. Comparing with our study, both demonstrated
the effectiveness of abiraterone acetate, with comparable PSA response rates of 49%
at 12 weeks in Cindolo et al's study and 65.7% in our study. Additionally, both studies
indicated a positive DCR, with Cindolo et al reporting a proportion of 71.4% and our
study showing 71.4%. The findings from both studies collectively support the notion
that abiraterone acetate is effective in treating mCRPC in real-world scenarios, highlighting
its value as a treatment option.[31 ]
This study has several limitations that need to be taken into account. First, it is
a single-center, retrospective study. Second, due to the limited number of eligible
patients from a single center, we were unable to provide an analysis of a larger sample
size. Due to retrospective nature of this study and limited sample size, it was difficult
to provide accurate Kaplan–Meier curves from the data. Despite these limitations,
the outcomes of this real-world study are consistent with the conclusions drawn from
earlier randomized controlled trials and real-world investigations. Our findings provide
evidence that generic abiraterone (Abiratred) is both well-tolerated and effective
for patients with advanced/metastatic prostate cancer. These results may have important
implications for the use of generic abiraterone in clinical practice.
Conclusion
This real-world study provides evidence that generic abiraterone (Abiratred) is both
well-tolerated and effective for patients with advanced or metastatic prostate cancer,
making it a promising option in real-world clinical settings.
