Abstract
Background/Aim: Novel hormone agents (NHA) have become important tools for the treatment of advanced prostate cancer. Among them, abiraterone and enzalutamide are two major regimens in the treatment of metastatic castration-resistant prostate cancer (MCRPC). The aim of this study was to evaluate the efficacy of both drugs in patients who had disease progression after androgen deprivation therapy (ADT), using our real-world database. Patients and Methods: We retrospectively analyzed MCRPC patients who received abiraterone and enzalutamide between October 2010 and October 2021. The associations between baseline demographics and clinical outcomes were evaluated. ADT was defined as luteinizing hormone-releasing hormone (LHRH) agonists, antagonists, or orchiectomy. Results: Of the 324 included patients, the median age was 77 years. Amongst them, 81 patients received chemotherapy-naïve abiraterone, 141 received post-chemotherapy abiraterone, 64 patients received chemotherapy-naïve enzalutamide and 38 patients received post-chemotherapy enzalutamide. The median overall survival was 43.6 months among all NHA-treated MCRPC patients. Pre-MCRPC ADT duration >25.31 months and enzalutamide use were each associated with a decreased risk of death (HR=0.54, 95% CI=0.39-0.75, p<0.001, and HR=0.53, 95% CI=0.33-0.87, p=0.012, respectively), while high-volume disease was associated with an increased risk of death (HR=1.53, 95% CI=1.10-2.21, p=0.007). Upfront chemotherapy and pre-MCRPC ADT duration of >21.03 months were each associated with an increased prostate-specific antigen (PSA) response after NHA treatment (OR=3.18, 95% CI=1.33-7.63, p=0.010, and OR=2.72, 95% CI=1.63-4.54, p<0.001, respectively). Conclusion: Our real-world data revealed the effectiveness of using both abiraterone and enzalutamide in the treatment of MCRPC patients. Long pre-MCRPC ADT duration and enzalutamide use were both associated with a decreased risk of death regardless of four different treatment sequences. Upfront docetaxel and longer pre-MCRPC ADT duration were each associated with an increased NHA PSA response rate.
Novel hormone agents (NHA) are defined as being an extensive androgen axis blockade when compared with conventional androgen deprivation therapies (ADTs) such as luteinizing hormone-releasing hormone (LHRH) agonists, antagonists, and other oral anti-androgens. Amongst them, abiraterone acetate and enzalutamide are two of the pioneers which have been shown to provide clinical benefits in metastatic castration-resistant prostate cancer (MCRPC) (1-4). Data from previous clinical trials in MCRPC chemotherapy-naïve and post chemotherapy has revealed only 4-6 months of net overall survival benefits when treatment involves using either abiraterone acetate or enzalutamide. Although new evidence taken from the Latitude and ARCHES trials has shifted the role of NHA to an earlier setting with regards to MCSPC, abiraterone acetate and enzalutamide still remain two major therapeutic agents for MCRPC patients (5, 6).
Several real-world patient features have demonstrated different overall survival or progression survival outcomes in advanced prostate cancer patients. Cheng et al. reported that high-volume prostate cancer is an independent risk factor for poor overall survival among Taiwanese metastatic prostate cancer patients (7). ADT duration prior to MCRPC was also reported to be an indicator of overall survival for NHA treatments (8, 9). Moreover, sequential treatment regimens such as other NHAs, docetaxel rechallenge, cabazitaxel, and radium-223 treatment have also been shown to be beneficial in MCRPC patients after first line therapy (10-13).
In order to evaluate the clinical benefits of using abiraterone acetate and enzalutamide in real-world MCRPC patients, we retrospectively collected patients from our hospital and performed a comprehensive statistical analysis.
Patients and Methods
Patients and treatments. This study was conducted through a retrospective chart review process with an internal validation and was approved by the institute review board of Taichung Veterans General Hospital (IRB No: CE20173B). Between October 2010 and October 2021, patients who received either abiraterone or enzalutamide during MCRPC treatment periods were included. Upfront docetaxel treatment at MCSPC status was permitted, while combination ADT with abiraterone or enzalutamide at MCSPC was excluded.
Study assessment. Four different treatment types for patients were included, chemotherapy-naïve abiraterone, post-chemotherapy abiraterone, chemotherapy-naïve enzalutamide and post-chemotherapy enzalutamide. The study end point was overall survival after MCRPC. Baseline patient characteristics included continuous variables such as age, Eastern Cooperative Oncology Group (ECOG) status, prostate-specific antigen (PSA) level at both MCRPC and first line treatment, PSA change between MCRPC and first treatment, MCRPC alkaline phosphatase level, MCRPC hemoglobin level, MCRPC baseline pain score, docetaxel treatment cycles, ADT duration prior to MCRPC, and follow-up duration. Other categorical variables included treatment types, Gleason score at initial diagnosis, biphosphate use during MCRPC period, present as de novo metastatic prostate cancer (mPC), high-volume or high-risk disease at mPC, docetaxel treatment, PSA response or decline after docetaxel, abiraterone or enzalutamide treatment, PSA response or decline after abiraterone or enzalutamide, cabazitaxel treatment, docetaxel rechallenge treatment, NHA rechallenge treatment, salvage prostatectomy or radiation therapy, radium-223 treatment, comorbidities during study periods such as diabetes, hyperlipidemia, dementia, neurological disorders, cardiovascular diseases, hypertension, thyroid disorders, ischemic heart disease, chronic obstructive pulmonary disease (COPD), liver diseases and chronic kidney diseases (CKDs). The recorded age of the patients was based on the time of MCRPC diagnosis. The definition of MCRPC was determined according to the PSA changes in Prostate Cancer Working Group 2 (PCWG2) (14). The pain score was recorded using numeric rating scales. Docetaxel treatment cycles were based on a 3-week schedule, with 75 mg/cm2 used as one cycle and some patients receiving 50 mg/cm2. A two-week schedule would be recorded as a two thirds cycle. For patients who had undergone previous upfront docetaxel treatments, their total cycles were taken into account. ADT duration was measured from the beginning date of LHRH agonists, antagonists or orchiectomy to the date that MCRPC was diagnosed. Follow-up duration was recorded as the beginning date of a patient’s first systemic therapy after MCRPC, to the date of death or last follow-up date. Gleason score was recorded the first time prostate cancer was diagnosed. De novo mPC was defined as metastatic prostate cancer confirmed during the initial diagnosis of prostate cancer. High-volume prostate cancer was defined according to the CHAARTED Trial which involved visceral metastases, or ≥4 bone metastases with at least one lesion located beyond the vertebral body and pelvis (15). The definition of high-risk disease was based on the LATITUDE study which featured at least two of the following three conditions, a Gleason score ≥8, visceral metastases, and at least three bone metastases. PSA response was defined as a post treatment PSA decline of ≥50% from pre-treatment PSA. PSA decline was defined as any PSA decrease after treatment when compared with pre-treatment. Docetaxel rechallenge was defined as the second or third docetaxel injection during the MCRPC treatment period. NHA rechallenge included at least one of the other NHA treatments during the study period, with apalutamide and darolutamide being permitted in this setting. Salvage prostatectomy or radiation therapy for prostate or metastatic bone lesions were recorded at this cohort. Comorbidities were recorded from a database search with any of the diagnoses coded during the study period.
Statistical analysis. The chi-square test was used for categorical variables as well as the treatment response rate comparison among four treatment strategies. Baseline patient characteristics and the treatment responses were analyzed using post hoc Fisher’s tests. All the continuous variables were presented by median (interquartile range) and the categorical variables by percentage. The overall survival curves were plotted using the Kaplan-Meier method. Univariate and multivariate Cox hazard proportional regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for association between variables and overall survival. Logistic regression was used for the estimation of odds ratio (OR) and 95% CI for association between variables and the NHA response. We used area under the curve (AUC) to test the pre-MCRPC ADT duration in overall survival and treatment response. The cut-off pre-MCRPC ADT duration was 25.31 months (AUC=0.633) and 21.03 months (AUC=0.643) in overall survival and treatment response analysis, respectively. The statistical significance threshold was set at 5% for each analysis and confidence interval. All statistical analyses were performed using SAS software version 9.2 (SAS Institute, Inc., Cary, NC, USA).
Results
There were 331 patients in our database who were receiving either abiraterone or enzalutamide after their diagnosis of MCRPC during the study period. Four patients discontinued follow-up treatment at our institute and three other patients who did not receive any survey after treatment were excluded. Finally, 324 patients were included in this analysis. Amongst them, 81 patients received chemotherapy-naïve abiraterone, while 141 received post-chemotherapy abiraterone. Sixty-four patients received chemotherapy-naïve enzalutamide, while 38 patients received post-chemotherapy enzalutamide.
The baseline characteristics and patient demographics are listed in Table I. The median age was 77 years amongst all patients. The median ECOG status was 0 and only 8.3% (27/324) patients were recorded ECOG 2. There were 77.3% of the patients (218 of 282, some patients had missing data) who had recorded a pathological Gleason score ≥8, and 78.4% (254/324) who had de novo mPC. Thirty-eight patients received upfront chemotherapy while being mPC diagnosed. Median pre-MCRPC ADT duration was 21.17 months. The median PSA level at MCRPC was 8.45 ng/ml. Median PSA at first treatment was 15.95 ng/ml, while PSA change between MCRPC and first treatment was 0. The median MCRPC alkaline phosphatase level was 117 U/l and the median hemoglobin level was 12.3 g/dl. In addition, median baseline pain score was only 2 among our population. High-volume prostate cancer accounted for 36.11% of the patients (117/324), while 41.98% of the patients (136/324) were recorded as high-risk disease. Median docetaxel chemotherapy cycles were 6 with 58.74% of chemotherapy patients (121/206) receiving ≥6 cycles of docetaxel treatment. Docetaxel PSA response was 54.11% (112/206).
Baseline characteristics and demographics of metastatic castration resistant prostate cancer patients (n=324).
There were 231 patients (71.3%) receiving abiraterone, with 9 of them (3.90%, 9/231) taking it as subsequent therapy after enzalutamide. There was a 47.81% PSA response rate among all abiraterone-treated patients, while PSA decline rate was 56.14%. PSA response and PSA decline from abiraterone treatment were both better in the chemo-naïve setting compared with post-chemo, 69.14% vs. 36.17% and 72.84% vs. 46.81%, respectively (post hoc Fisher’s test, p<0.001 in both). The median abiraterone treatment duration was 7.21 months (11.73 months and 6.29 months in the chemo-naïve and post-chemo groups, respectively).
One hundred and thirty-four patients received enzalutamide, with 32 of them coming from post abiraterone treatment. PSA response and PSA decline rate after enzalutamide treatment was 58.96% and 73.13% respectively. Median enzalutamide treatment duration was 9.75 months. The median pre-enzalutamide treatment PSA was 19.42 ng/ml, while it was significantly higher in the post-chemo abiraterone group compared to the post-chemo enzalutamide group (91.58 ng/ml vs. 11.34 ng/ml, post hoc, p=0.004). The baseline PSA level was higher in the post-chemo abiraterone group because abiraterone was the first drug applied in clinical practice which included previously untreated high-PSA patients.
Biphosphate was not routinely used among our population and only 52.78% (171/324) patients received bone protecting therapies. Thirty-three (10.19%) patients received cabazitaxel as subsequent treatment, while 27 (8.33%) and 41 (12.65%) patients underwent docetaxel and NHA rechallenge therapy, respectively.
Cardiovascular diseases and hypertension accounted for the most commonly associated comorbidities amongst all abiraterone and enzalutamide treated patients, 50.93% and 38.27% respectively. Ischemic heart diseases were recorded to be significantly higher in the chemo-naïve abiraterone group, compared to the post-chemo abiraterone and enzalutamide groups (post hoc 35.8% vs. 17.73%, p=0.02; 35.8% vs. 13.16%, p=0.047, respectively).
The number of total deaths was 183 (56.48%) with most occurring in the post-chemo abiraterone group (119, 84.4%). Median follow-up duration was 28.91 months and the median overall survival of total 324 patients was 43.6 months (Figure 1).
Overall survival of 324 patients receiving novel hormone agents for the treatment of metastatic castration resistant prostate cancer.
Table II shows the Cox hazard proportional regression model, where pre-MCRPC ADT duration more than 25.31 months and enzalutamide use were each associated with a decreased risk of death (HR=0.54, 95% CI=0.39-0.75, p<0.001, and HR=0.53, 95% CI=0.33-0.87, p=0.012, respectively), while high-volume disease was associated with an increased risk of death (HR=1.53, 95% CI=1.10-2.13, p=0.012). For prediction of NHA treatment response, upfront chemotherapy and pre-MCRPC ADT duration more than 21.03 months were each associated with an increased PSA response after NHA treatment, (OR=3.18, 95% CI=1.33-7.63, p=0.010, and OR=2.72, 95% CI=1.63-4.54, p<0.001, respectively) (Table III). In summary, the treatment response rate in the first line setting ranged from 55.32% to 71.88% and it gradually declined with each subsequent treatment among the four different treatment groups (Figure 2).
Univariate and multivariate analysis for overall survival after metastatic castration-resistant prostate cancer (MCRPC).
Univariate and multivariate analysis for treatment response of novel hormone agents (NHA).
Treatment response rate among four different sequences. The responses to first-line treatment showed no statistical difference among the four sequences (p=0.053). The responses to second-line treatment were significantly higher in the chemo-naïve abiraterone (56.25%), as well as in post-chemo enzalutamide group (65.79%) compared to the chemo-naïve enzalutamide group (18.18%, overall p=0.002). The responses to third-line treatment did not differ among the four different sequences (p=0.944). The comparison was calculated by the chi-square test.
Discussion
Abiraterone and enzalutamide are two major NHA used for the treatment of MCRPC. In this retrospective single-center study, we evaluated the efficacy of these agents in Taiwanese MCRPC patients that had disease progression after ADT. Enzalutamide provided overall survival benefit to MCRPC patients. Pre-MCRPC ADT duration and high-volume disease were also independent predictors for overall survival. Although the retrospective database consisted of heterogenous treatment sequences and patient characteristics, it revealed a real-world effectiveness of NHA in the treatment of MCRPC patients comparable to the COU-AA-302 and the Prevail trials (median overall survival 34.7 months and 35.3 months respectively) (16, 17).
The effectiveness of NHA in the Asian MCRPC population had been reported in several series (18, 19). Our median overall survival was comparable to other series, and it was in line with the survival advantage among Asian population in metastatic prostate cancer, reported by Siegel et al. (20). Race differences, health care accessibility, and social awareness may contribute to this finding.
Several real-world series have shown the association between clinical parameters and overall survival in MCRPC patients during NHA treatments. Chi et al. found 6 clinical parameters including lactate dehydrogenase > upper limit of normal, ECOG status of 2, presence of liver metastasis, albumin ≤4 g/dl, alkaline phosphatase > upper limit of normal and time from start of ADT to initial treatment ≤36 months as independent factors to overall survival in post-chemo abiraterone treated MCRPC patients (21). Marar et al. found that first line treatment with abiraterone during MCRPC showed decreased overall survival compared to enzalutamide among non-Hispanic white patients (22). In our series, the longer pre-MCRPC ADT duration >25.31 months was associated with better OS, which was in line with Chi et al. and other real world series results and was considered as the phenomenon of androgen receptor affinity (8, 23, 24).
Enzalutamide showed potency in the treatment of MCRPC in chemo-naïve and post-chemo settings. Thirty-two patients (14.41%) in the abiraterone treatment group received enzalutamide as a subsequent treatment, with 8 of them (25%) having a PSA response. However, only 9 patients received abiraterone as a subsequent treatment after enzalutamide, and 2 of them had a PSA response (22.2%). Although the subsequent treatment response rate seemed comparable using abiraterone-enzalutamide and enzalutamide-abiraterone sequencing, enzalutamide use was an independent factor associated with 47% death risk reduction compared to non-enzalutamide users. This result is in agreement with the phase 2 trial performed by Khalaf et al., which revealed the potency of enzalutamide during NHA sequential treatment in MCRPC (25) and suggested that using a strategy of abiraterone followed by enzalutamide could improve clinical benefits.
Amongst our patients, the abiraterone-related strategy accounted for 68.52% (222/324) of total patients. It reflected the drug approval lag amongst post-chemo and chemo-naïve abiraterone or enzalutamide indications as well as some physicians’ preferences.
The treatment response rate was shown to gradually decline with each subsequent treatment therapy (Figure 2), which is in line with the current clinical practice for MCRPC management using NHA as the first line option. Although the cross resistance between docetaxel and enzalutamide has been observed in literature, limited response rate can still be found while using docetaxel as the second line treatment (10). Taking into consideration the expensive novel drugs such as cabazitaxel, docetaxel can be used as an alternative.
Post-chemo NHA treatment was the first clinical application after docetaxel. Abiraterone acetate and enzalutamide after docetaxel chemotherapy resulted in overall survival benefits, compared to the placebo groups, according to the COU-AA-301 and the AFFIRM trials, respectively (1, 3). Both study groups had a median treatment duration of approximately 8 months (abiraterone 32.1 weeks and enzalutamide 8.3 months), which was similar to our data (abiraterone 6.29 months and enzalutamide 12.8 months). The median docetaxel treatment cycle was 8.5 in the AFFIRM trial and 6 in our series. Although NHA showed a wide application in the treatment of advanced prostate cancer, docetaxel still played an important role in our practice.
The COU-AA-302 trial and PREVAIL trial both showed an overall survival benefit from abiraterone and enzalutamide in chemo-naïve MCRPC (2, 4). The median overall survival was 34.7 months and 35.3 months in the abiraterone and enzalutamide treatment arms, respectively. The median PSA progression duration was 11.1 months and 11.2 months when administering abiraterone and enzalutamide, respectively. Our data showed comparative results, with a median overall survival of 47.1 months and 51.5 months in the abiraterone and enzalutamide chemo-naïve treatment groups, respectively and a median PSA progression duration of 11.73 and 11 months, respectively.
Gleason score 5 was reported to be an independent risk factor for poor overall survival in metastatic castration sensitive prostate cancer (26). In our series, neither overall survival nor NHA treatment response differed among all grade subdivisions. Borno et al. reported a better overall survival benefit among de novo metastatic castration-sensitive prostate cancer patients when compared with recurrent disease from the CaPSURE database (27). There were 78.4% de novo MCSPC patients in our series and the impact was not significant in our analysis.
Upfront chemotherapy has previously shown a significant improvement in overall survival in high volume MCSPC patients (15). In our series, upfront chemotherapy improved the NHA response rate (OR=3.18, p=0.010), but not overall survival. Two reasons may account for these results. First, 63.16% (24/38) of upfront chemotherapy patients received enzalutamide therapy, with the overall survival benefit masked by enzalutamide. The other reason is that docetaxel can block antigen receptor (AR) accumulation in the nucleus and induce downstream transcription arrest which overlaps the pathway of NHA (28). While upfront docetaxel can stabilize AR activation in the MCSPC stage, it may also correlate to the sensitivity of NHA in the MCRPC stage. A similar rationale was also found in the PEACE-1 trial (29). Loriot et al. and our previous study both showed similar AR axis sensitivity using ADT duration before MCRPC as a predictor (8, 9, 30). Both studies used a real-world cohort and found that a longer time to castration resistance could predict a higher percentage of PSA response using enzalutamide and abiraterone.
Cabazitaxel and radium-223 both provided clinical benefits towards the rapid progression of MCRPC and bone health protection in CARD and ALSYMPCA trials, respectively (12, 13). However, we were unable to find any overall survival benefit using this retrospective, small population cohort study.
Comorbidities were not uncommon amongst our study patients. The chemo-naïve abiraterone group had a significantly higher percentage of ischemic heart diseases when compared to the post-chemo abiraterone and enzalutamide groups (35.8% vs. 17.73% and 13.16%, p=0.02 and p=0.047, respectively). Tracing back to the medical records, pre-existing coronary heart diseases were high in this group (18.52%, 15/81). This finding may correspond to certain meta-analysis studies regarding the association between NHA and cardiovascular diseases (31).
Limitations within this study include a small population, its retrospective nature, heterogeneous patient characteristics and health insurance-oriented treatment selection bias.
In conclusion, our real-world experience revealed that both abiraterone and enzalutamide were comparatively effective for the treatment of MCRPC patients and upfront chemotherapy showed higher PSA response rate among NHA treated patients. Further studies to evaluate the patient selection criteria for the early use of docetaxel chemotherapy are important for clinical practice.
Acknowledgements
This work was supported by the Ministry of Science and Technology, Taiwan. Grant number: MOST 109-2314-B-075A-007-MY3
Footnotes
Authors’ Contributions
Jian-Ri Li, Sheng-Chun Hung contributed to study design. Shian-Shiang Wang, Chuan-Shu Chen, Cheng-Kuang Yang, Kun-Yuan Chiu, Shu-Yen Chen contributed to data collection. Statistical analysis was performed by Kevin Lu and Chiann Yi Hsu. The manuscript was written by Jian-Ri Li and revised by Kevin Lu and Chen-Li Cheng.
Conflicts of Interest
The Authors have declared no conflicts of interest.
- Received May 26, 2022.
- Revision received July 14, 2022.
- Accepted August 9, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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