Efficacy of Enzalutamide for Patients with Castration-Resistant Prostate Cancer in Real-World Clinical Practice: A Retrospective Single Institutional Analysis with 5-Year Follow-up

doi:10.21203/rs.3.rs-1594965/v1

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Efficacy of Enzalutamide for Patients with Castration-Resistant Prostate Cancer in Real-World Clinical Practice: A Retrospective Single Institutional Analysis with 5-Year Follow-up

https://doi.org/10.21203/rs.3.rs-1594965/v1

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Background

Enzalutamide’s efficacy and prognosis for patients with castration-resistant prostate cancer (CRPC) in real-world clinical practice have not been sufficiently examined.

Methods

We retrospectively investigated data on 135 consecutive CRPC patients who had received enzalutamide. Prostate-specific antigen (PSA) response ( > = 50% PSA decline from baseline), progression-free survival (PFS), overall survival (OS), and poor prognostic factors related to PFS and OS were analyzed.

Results

The median follow-up period was 63 months. Of all, 46 cases were post-chemo, 90 were metastatic, and 38 were prior-abiraterone acetate use. PSA responses were observed in 55.6% of patients, and no statistically significant differences between chemo-naive and post-chemo groups were noted. The median PFS of all CRPC patients was 301 days (95% CI, 239–363); in patients with prior abiraterone acetate use, PFS was shorter than the others (HR 0.56, 95% CI, 0.36–0.83, p = 0.010). Median OS from initiation of enzalutamide was 790 days and shorter in patients in the post-chemo and metastatic groups. On the other hand, the median OS from CRPC diagnosis was 1514 days and shorter only in the metastatic group (HR 0.44, 95% CI, 0.19–1.01, p = 0.0052). In multivariate analysis, the time between androgen deprivation therapy (ADT) initiation and CRPC diagnosis being < 20 months (i.e., time to CRPC < 20 mo.), prior-docetaxel use, and prior-abiraterone acetate use were risk factors for shorter PFS. Time to CRPC < 20 mo. and prior-docetaxel use were factors influencing shorter OS from initiation of enzalutamide, and only time to CRPC < 20 mo. was related to shorter OS from CRPC diagnosis.

Conclusions

This study revealed the efficacy of enzalutamide for CRPC patients in a real-world clinical setting. We could use enzalutamide at any time during CRPC treatment. These findings are valuable for clinical decision-making during CRPC patients’ treatment.

Enzalutamide

CRPC

Overall survival

Progression-free survival

Second generation antiandogens

Enzalutamide is an androgen-receptor signaling axis-targeting (ARAT) agent, demonstrating significant benefit in metastatic hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC) and is considered a second-generation anti-androgen.[1] [2] [3] [4] [5] Previous major multinational, double-blind, phase III clinical trials—the PROSPER, PREVAIL, and AFFIRM trials—provided evidence supporting enzalutamide’s significant anti-tumor activity compared with placebo for patients with non-metastatic and metastatic CRPC under the chemo-naive and post-chemo treatment plans.[3] [4] [5] However, in real-world clinical practice, what is the efficacy of this novel anti-androgen agent? Does efficacy change with clinical trials? How does enzalutamide’s efficacy vary among patients’ backgrounds? In this study, we investigated enzalutamide’s treatment status, response, and prognostic factors based on our real-world clinical practice data.

We retrospectively reviewed the medical records of 135 consecutive patients with CRPC who had enzalutamide prescribed as standard-of-care at our institution from July 2014 through October 2021. All patients were prescribed enzalutamide for at least one month. Previous androgen deprivation therapy had been in the form of medical castration. CRPC was defined according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria[6] using conventional radiographic modalities such as computed tomography (CT) and bone scans. All patients were evaluated for clinical symptoms and PSA values every month after enzalutamide administration. Imaging studies’ scheduling, including CT and bone scans, depended on the treating physicians’ discretion, based on new symptoms or PSA increase.

Patients’ baseline characteristics, demographic data, treatment sequence related to enzalutamide administration, treatment response, prognosis, and clinical outcome of PSA response, progression-free survival (PFS), overall survival (OS), and predictive factors of shorter PFS and OS were analyzed. We defined chemotherapy as the use of docetaxel. PFS and OS were analyzed prior to chemotherapy and in metastatic or prior-abiraterone acetate use settings.

PFS was defined as the interval of enzalutamide administration from enzalutamide initiation to discontinuation due to any cause, such as PSA progression, radiographic progression, or new symptoms, including the progression of other diseases. OS was defined as the time from initial administration of enzalutamide or from CRPC diagnosis until death from any cause. Factors predictive of shorter PFS and OS were elucidated from patients’ ages, pathological findings, initial PSA values, time from the beginning of androgen deprivation therapy (ADT) to CRPC (= time to CRPC), metastatic status, prior-docetaxel use, and prior-abiraterone acetate use before enzalutamide administration.

Baseline treatment groups were compared using the Mann-Whitney U test. PSA response was defined as a reduction in the PSA level from baseline as a maximal PSA change during enzalutamide treatment using water-plot analyses. Differences among treatment groups were analyzed using Fisher’s exact test. Toxicity was assessed according to the National Cancer Institute of the National Institutes of Health (NIH) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0[7]. We estimated PFS and OS of time-to-event distributions using Kaplan-Meier curves and log-rank tests. Univariate and multivariate analyses were performed by the Cox proportional hazards model. All statistical tests were two-sided, with p < 0.05 considered statistically significant. Statistical analyses were done using SPSS Statistics ver. 28.0.1 software. This study was conducted with approval from the institutional review board (2021353) and carried out in accordance with the Declaration of Helsinki and ethical guidelines regarding clinical studies.

Patients’ clinical characteristics

Patient characteristics and demographics are given in Table 1. Among the 135 study participants with CRPC who had received enzalutamide, 89 were chemo-naive, and 46 were post-chemo patients. The median age at CRPC progression of all patients was 76 years (IQR, 70–79), and the median age of post-chemo patients was 73 years (IQR, 67-78), which was significantly younger than those of chemo-naive patients at 77 years (IQR, 71–81) (p = 0.0002). The median follow-up period for all patients, chemo-naive patients only, and post-chemo patients only were 63 months (IQR, 33–108), 75.5 months (IQR, 38.3–111.8), and 55.0 months (IQR, 30.3–96.8), respectively. All patients underwent ADT combined with first-generation anti-androgen agent bicalutamide administration before CRPC. No patients received up-front androgen-receptor signaling axis-targeting agent (ARAT) or chemotherapy in the hormone-sensitive setting.

The median time to CRPC of all, chemo-naive, and post-chemo patients were 19 (IQR, 10–50), 26.0 (IQR, 11–67), and 12.0 months (IQR, 6.0–28.8), respectively. After the CRPC setting, 17.0% (23/135), 24.7% (22/89), and 2.2% (1/46) of patients were diagnosed with non-metastatic CRPC. The rate of localized therapy, prior-abiraterone acetate use before enzalutamide administration, and bone modifying agents (BMA) treatment with enzalutamide were not significantly different between chemo-naive and post-chemo CRPC groups. The median serum PSA value of post-chemo patients at initiation of enzalutamide (36.7 ng/mL) was significantly higher than that of chemo-naive patients (10.2 ng/mL) (p = 0.0005).

PSA response

The maximum PSA changes during enzalutamide treatment are depicted in a waterfall plot chart (Fig. 1A-C). PSA responses were observed in 80.0% (108/135) of all, 84.3% (75/89) of chemo-naive, and 71.7% (33/46) of post-chemo CRPC patients. There was no statistically significant difference in PSA response rate between the chemo-naive and post-chemo groups (p = 0.085; Fisher’s exact test). On the other hand, a PSA response rate of >= 50% decline from baseline was observed in 55.6% (75/135) of all, 62.9% (56/89) of chemo-naive, and 41.3% (19/46) of post-chemo CRPC patients, respectively. A PSA response rate of > 50% was significantly higher in chemo-naive CRPC patients than post-chemo CRPC patients (p = 0.017).

Causes of treatment discontinuation and adverse events

Among all 135 patients, 75.6% (102/135) discontinued enzalutamide therapy. The causes of discontinuation included PSA progression 82.5% (84/102), radiographic progression 2.0% (2/102), adverse event 2.9% (3/102), progression of other diseases 2.9% (3/102), and deterioration of general condition 9.8% (10/102) (Table 2). Notably, three patients who experienced adverse events during enzalutamide use experienced symptoms of fatigue (grade 2), itchy skin (grade 2), and rash (grade 2). These events improved after stopping enzalutamide treatment.

Progression-free survivals

The median PFS of all CRPC patients was 301 days (95% CI, 239–363) (Fig. 2A). The median PFS of chemo-naive and post-chemo CRPC patients were 362 days (95% CI, 279–444) and 245 days (95% CI, 174–316), respectively, which was statistically significantly different between the two groups (HR 0.48, 95% CI, 0.32–0.74, p < 0.001) (Fig. 2B). There was no significant difference in the median PFS between non-metastatic patients at 392 days (95% CI, 287–497) and metastatic patients at 266 days (95% CI, 204–328) CRPC patient groups (HR 0.61, 95% CI, 0.35-1.06, p = 0.079) (Fig. 2C). The median PFS for patients with prior abiraterone acetate use was 161 days (95% CI, 60.5–261), shorter than the others at 350 days (95% CI, 290–410) (HR 0.56, 95% CI, 0.36–0.83, p = 0.010) (Fig. 2D).

Overall survivals from initiation of enzalutamide

The median OS from initiation of enzalutamide was 790 days (95% CI, 667–913 days) for all CRPC patients (Fig. 3A). The median OS of chemo-naive and post-chemo CRPC patients were 1142 days (95% CI, 579–1704) and 540 days (95% CI, 467–613), respectively, which was statistically significantly different between the two groups (HR 0.47, 95% CI, 0.28–0.79, p = 0.004) (Fig. 3B). There was a significant difference in the median OS between non-metastatic (1422 days (95% CI, 1246 – 1597)) and metastatic (730 days (95% CI, 667–913)) CRPC patient groups (HR 0.36, 95% CI, 0.16–0.86, p = 0.020) (Fig. 3C). Additionally, there was a significant difference in the median OS between patients with prior-abiraterone acetate use at 478 days (95% CI, 375–580) and those without at 869 days (95% CI, 696–1042) patient (HR 0.85, 95% CI, 0.49–1.48, p = 0.56) (Fig. 3D).

Overall survivals after CRPC setting

The OS from the time of CRPC diagnosis was also analyzed. The overall median OS from CRPC diagnosis was 1514 days (95% CI, 1339–1689 days) (Fig. 4A). The median OS of chemo-naive and post-chemo CRPC patients were 1968 days (95% CI, 1191–2754) and 1273 days (95% CI, 984–1562) from CRPC diagnosis, respectively, which was not a statistically significant difference between the two groups (HR 0.70, 95% CI, 0.43–1.13, p = 0.15) (Fig. 4B). The median OS in patients with non-metastatic (not reached) tended to be longer than that of metastatic CRPC patients at 1426 days (95% CI, 1126-1725 days) but did not reach statistical significance (HR 0.44, 95% CI, 0.19–1.01, p = 0.052) (Fig. 4C). The median OS of patients was 1426 days (95% CI, 1160 –1692 days) with prior abiraterone acetate use and 1514 days (95% CI, 1100–1927 days) without prior abiraterone acetate use before enzalutamide treatment, which was also not a statistically significant difference (HR 1.00, 95% CI, 0.60–1.67, p = 0.99) (Fig. 4D).

Risk factors of enzalutamide therapy related to PFS and OS

To search for the variables predicting shorter PFS and OS after initiation of enzalutamide for CRPC patients, we performed Cox proportional hazards analyses (Table 3, 4 and 5). Regarding PFS, time from ADT therapy initiation to CRPC diagnosis < median value (20 months), prior-docetaxel use, and prior-abiraterone acetate use were risk factors identified in univariate analysis. These three were also risk factors identified by multivariate analysis (Table 3). On the other hand, regarding OS from initiation of enzalutamide, time to CRPC < 20 mo., non-metastatic CRPC status, prior-docetaxel use, and prior-abiraterone acetate use were risk factors in univariate analysis, and only time to CRPC < 20 mo. and prior-docetaxel use were risk factors in multivariate analysis (Table 4). Interestingly, in multivariate analysis, only time to CRPC < 20 mo. was associated with unfavorable OS from the time of CRPC diagnosis for the patients treated with enzalutamide (Table 5).

In this single-center retrospective study of 135 patients with CRPC treated with enzalutamide for the first time, we identified the efficacy of enzalutamide in real-world clinical practice. From our clinical data of median follow-up period of 63 months, PSA response rate was not different with or without prior-chemotherapy, PFS was different among patients’ status such as metastatic, prior-chemotherapy, and prior-abiraterone acetate use. However, OS was different only for patients with metastatic disease. Additionally, time to CRPC < 20 mo. was the only poor prognostic factor of OS measured from the time of CRPC diagnosis.

From the maximum PSA changes during enzalutamide treatment, our results revealed no statistically significant difference in PSA response rate between chemo-naive and post-chemo groups (Fig. 1A-C). This suggests that because not anti-androgen (AR)-mediated mechanisms are associated with chemotherapy resistance, there is room for enzalutamide to work[8]. In our real-world clinical practice, all CRPC patients received at least one prior anti-androgen treatment (Table 1). This would be a reason for worse than a > 50% PSA decline rate compared with previous clinical trials in both 62.9% of chemo-naive (78% in PREVAIL) and 41.3% of post-chemo (54% in AFFIRM) patients’ status.

From the Japanese sub-analysis, the PREVAIL study also demonstrated that 60.7% of patients experienced a ≥ 50% decline from baseline PSA in the enzalutamide group[9]. In other words, this discrepancy from clinical trials might reflect the potential efficacy of vintage hormonal agents. However, instead of vintage, non-steroidal anti-androgen agents, which target only AR binding to androgens, the novel androgen-receptor signaling axis-targeting agents of enzalutamide attacks AR signaling at multiple steps, not only binding to androgens but also AR translocation to the cell nucleus and AR binding to deoxyribonucleic acid (DNA).[10]

From PFS analysis after initiation of enzalutamide, the efficacy of enzalutamide is expected to be better in patients within the chemo-naive group than the post-chemo group (Fig. 2B), the same in both the non-metastatic and metastatic CRPC patient groups (Fig. 2C), and worse in patients with prior-abiraterone acetate use (Fig. 2D). However, we must consider that the non-metastatic patient status of this study was defined using conventional radiographic modalities such as CT and bone scans. Fendler et al. demonstrated that 55% of patients previously diagnosed with non-metastatic high-risk CRPC by conventional imaging experienced detection of any metastatic region by the novel radiographic modality of Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET)[11]. Post-chemo CRPC patients’ backgrounds included younger age, shorter time from primary ADT to CRPC, higher initial PSA value, and a higher rate of prior-abiraterone acetate use (Table 1), meaning that physicians tended to precede higher-risk patients with chemotherapy. As in previous studies,[12] [13] this study also revealed that the PFS of enzalutamide was decreased in patients with prior-abiraterone use (Fig. 4D).

Regarding OS, we analyzed both the time from enzalutamide initiation and CRPC diagnosis (Fig. 3, 4). Though median OS in patients with non-metastatic disease was longer than in metastatic CRPC patients, there were discrepancies among patients with or without prior chemotherapy and prior abiraterone acetate use between OS measured from enzalutamide initiation versus CRPC diagnosis (Fig. 4). These results suggested that enzalutamide efficacy affected clinical status rather than treatment sequence. As previously revealed, non-metastatic CRPC is a fatal disease, but the clinical OS was longer than the metastatic CRPC state.[14 15] The efficacy of enzalutamide was more promising for patients who had not been pre-treated with docetaxel or abiraterone acetate, but the overall impact on prognosis in treatment sequence was low.

In this study, we identified that time to CRPC < 20 mo., prior-docetaxel use, and prior-abiraterone acetate use were poor prognostic factors of PFS by both univariate and multivariate analysis (Table 3). All our patients received only first-generation anti-androgen agents before CRPC. Therefore, the time to CRPC seems to reflect potential disease progression and enzalutamide efficacy period. On the other hand, poor prognostic factors influencing OS from initiation of enzalutamide were the time to CRPC < 20 mo. and prior-docetaxel use. Variations in patients’ backgrounds possibly led to this result, in addition to disease progression potential. Chemo-selected patients experienced not only shorter time to CRPC, but also selected enzalutamide in the late phase of treatment sequence compared to chemo-naive patients (Table 1).

Prior studies had reported the efficacy of sequential use of abiraterone acetate and enzalutamide on metastatic chemo-naive CRPC patients. Their results suggested that these two ARAT treatment sequences did not affect OS, except for PFS, which was higher when enzalutamide was used as a second-line ARAT.[15] [16] Though our study included all CRPC patients treated with enzalutamide, multivariate analysis revealed prior-abiraterone acetate use was a poor prognostic factor for PFS, but not for OS from initiation of enzalutamide. The time to CRPC < 20 mo. was the only poor prognostic factor of OS when measured from CRPC diagnosis, per multivariate analysis. These findings suggested no other treatment options negatively affect enzalutamide treatment.

This study has some limitations that should be interpreted. First, this was a retrospective study involving a small number of patients in a single institution. Second, treatments, scheduled imaging, and follow-up period protocols were not uniform because of the study’s retrospective nature. Third, some candidate factors of cancer prediction, such as PS, were not incorporated into this study due to missing values. Finally, the dose/adherence of the enzalutamide was not considered in the present study. Therefore, a simple comparison between our results and clinical trials might be difficult. However, despite these limitations, our study represents enzalutamide’s efficacy and influence on patient prognosis at a 5-year follow-up and reflects current real-world clinical practice.

In conclusion, this study demonstrated enzalutamide’s efficacy and potential influence on prognosis for patients with CRPC in the real-world clinical setting. We identified no limitations for enzalutamide use in a CRPC treatment sequence, except for PFS on prior-abiraterone use, OS from initiation of enzalutamide in post-chemo and metastatic status, and OS when measured from CRPC diagnosis on metastatic status. We believe these data are valuable to both physicians and patients when making a CRPC treatment strategy in our real-world clinical practice.

Ethics approval and consent to participate

Participants provide informed consent to participate in these studies. All the steps/ methods were performed in accordance with the relevant guidelines and regulations and all experimental protocols and ethical consent of this study were approved by Ethics Committee at Kansai Medical University Hospital (reference number: 2021353)

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Competing interests

The authors declare no conflicts of interest.

Funding

None

Authors’ contributions: Hisanori Taniguchi: Conceptualization, Methodology, Formal analysis, Data curation, Writing-Original draft preparation. Masaaki Yanishi: Writing -Review and editing. Ryoichi Saito: Writing -Review and editing. Hidefumi Kinoshita: Supervision

Acknowledgments: The authors thank Victoria Hamilton from Wordvice.com for editing a draft of this manuscript.

Authors’ information

¹Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan

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Tables 1 to 5 are available in the Supplementary Files section.

No competing interests reported.

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Efficacy of Enzalutamide for Patients with Castration-Resistant Prostate Cancer in Real-World Clinical Practice: A Retrospective Single Institutional Analysis with 5-Year Follow-up

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Background

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Background

Methods

Results

Discussion

Conclusions

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Tables

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Supplementary Files

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