J Urol Oncol > Volume 22(1); 2024 > Article
Lim, Cho, Chung, Song, Kang, Sung, Jeon, Jeong, Seo, Jeon, and Park: Enzalutamide Maintenance Following Docetaxel in Metastatic Castration-Naive Prostate Cancer: A Pilot Feasibility Study

Abstract

Purpose

To assess the feasibility and short-term efficacy of maintenance enzalutamide following first-line docetaxel plus androgen deprivation therapy (ADT) in patients with high-volume, metastatic castration-naive prostate cancer (mCNPC).

Materials and Methods

The present study included 38 consecutive patients with mCNPC who did not have disease progression with ADT plus docetaxel between October 2022 and October 2023. Patients received a switch maintenance therapy with enzalutamide until progression, unacceptable toxicity, or patient withdrawal. Endpoints included time to prostate-specific antigen (PSA) progression and safety.

Results

Among the 38 patients, the median age was 68 years, and the most frequently observed metastatic site was bone (n=36), followed by lymph nodes (n=28), lung (n=8), and liver (n=1). The median duration of firstline docetaxel was 2.8 months (range, 2.7-5.0 months). At the time of commencing maintenance enzalutamide, the median PSA was 3.2 ng/mL (range, 0.01-258 ng/mL). Maintenance enzalutamide was generally welltolerated. A total of 11 patients (28%) discontinued enzalutamide, and the main reasons included adverse events (prolonged fatigue of grade 1 or 2, n=6), disease progression (n=3) and financial burdens (n=2). Median time to PSA progression was not reached, and 93% were PSA progression-free at 12 months.

Conclusions

Maintenance enzalutamide is a feasible treatment option with potential clinical benefit for patients with high-volume mCNPC who were progression-free after first-line ADT+docetaxel.

INTRODUCTION

In Korea, prostate cancer is one of the greatest growing cancers, with an incidence of >10,000 cases annually [1]. If a patient with prostate cancer develops or is diagnosed with metastatic disease, androgen deprivation therapy (ADT), which includes bilateral orchiectomy or medical castration with gonadotropin-releasing hormone agonists/antagonists can provide palliation of symptoms and prolong survival [2]. More recently, based on findings from clinical trials [3-8], guidelines have established the addition of docetaxel or novel androgen receptor targeting agents (ARTAs; i.e., abiraterone acetate, enzalutamide, or apalutamide) to ADT as the standard of care for those with metastatic castrationnaive prostate cancer (mCNPC) [9].
Although the long-term follow-up of clinical trials confirmed the benefit of adding docetaxel to ADT persisted regardless of metastatic burden [10], it is suggested that docetaxel might be under-used in clinical practice [11]. Use of docetaxel plus ADT in mCNPC setting is limited to patients with high-volume disease, provided they are willing and fit enough to receive cytotoxic chemotherapy. A major challenge with docetaxel is balancing the toxicity with clinical benefit. Duration of first-line docetaxel is limited to 4 to 6 months [3,4]. Therefore, there is a growing interest in switch maintenance therapy as a strategy for prolonging the benefit with first-line docetaxel while minimizing toxicity. In phase III trials involving first-line enzalutamide in mCNPC (ENZAMET and ARCHES) [6,7], prior treatment with docetaxel was permitted. Based on these considerations, from Oct 2022, we adopted a maintenance therapy with enzalutamide following 6 to 8 cycles of docetaxel as an institutional standard regimen for patients with high-volume, high-risk mCNPC. The present study was conducted to evaluate the feasibility of the regimen in anticipation of initiating a prospective, formal phase II study.

MATERIALS AND METHODS

We retrospectively collected and reviewed the medical records of 38 men with mCNPC who did not have disease progression with first-line ADT plus 6 to 8 cycles of docetaxel between Oct 2022 and Oct 2023. Enrolled patients had histologically confirmed prostate adenocarcinoma, documented metastatic disease before the receipt of ADT and first-line docetaxel for high-volume disease, no disease progression (i.e., no prostate-specific antigen [PSA] elevation and no evidence of progression on imaging studies) after 6 to 8 cycles of docetaxel chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and acceptable major organ functions to receive enzalutamide. High-volume disease was defined as bone metastases beyond the axial skeleton and/or visceral involvement, regardless of PSA level. The choice of first-line docetaxel was determined by a multidisciplinary urologic oncology team composed of urologists, radiologists, pathologists, radiation and medical oncologists.
Patients and initial tumor characteristics, docetaxel treatment duration, intervening therapies, and clinical outcomes were recorded. Analytical data with potential prognostic value, PSA decline and time to PSA progression were collected for both first-line docetaxel and maintenance enzalutamide treatments. First-line treatment consisted of docetaxel 20-25 mg/m2/week biweekly or tri-weekly regimen. Oral prednisone was given at a dose of 5 mg twice daily. After 6 to 8 cycles of docetaxel, clinical response was evaluated with PSA level, computed tomography scans, bone scans, or by the same tests that were initially used to stage the tumor. Patients without evidence of disease progression were eligible to switch to maintenance enzalutamide 160 mg orally per day. At the same time, patient who had not undergone surgical castration were required to continue ADT. The adverse events were recorded and graded according to the National Cancer Institute criteria (NCI-CTCAE). Endpoints of the present retrospective study included the PSA and radiologic responses, and safety during maintenance enzalutamide. PSA response and progression were defined as a >50% decline from baseline, and as an increase >25% and >2 ng/mL, respectively. Radiologic response and progression were evaluation according to the PCWG (Prostate Cancer Clinical Trials Working Group 2) criteria [12]: if a patient had no measurable lesions other than bone metastases, then the response was only classified as stable disease or disease progression. All statistical analyses were performed using R for Windows v2.11.1 (https://www.r-project.org).

RESULTS

The baseline patient characteristics and outcomes relating to prior docetaxel therapy are listed in Table 1. The duration of first-line docetaxel was 2.8 months (range, 2.7-5.0 months). All 38 patients had a PSA response with docetaxel, and radiologic responses were seen in 21 patients (58%). With ADT plus docetaxel, their PSA value was decreased from a median of 222.0 ng/mL (range, 3.3-10,000 ng/mL) to 3.2 ng/mL (range, 0.01-258.0 ng/mL). Most patients had metastases confined to bone and/or lymph nodes. Nine patients (24%) had visceral metastases (lung and/or liver). At the start of enzalutamide, their median age was 68 years (range, 46-82 years) and 47% had symptomatic (i.e., ECOG performance status of 1) disease.
With a median follow-up duration of 10 months (95% confidence interval, 9-12), 27 patients (71%) were still receiving maintenance enzalutamide. The main reasons for discontinuation of enzalutamide included adverse events (prolonged fatigue of grade 1 or 2, n=6), disease progression (n=3) and financial burdens (n=2). Two patients received a subsequent anticancer therapy: rechallenge docetaxel (n=1) and cabazitaxel (n=1). Maintenance enzalutamide was generally well-tolerated: adverse events of any grade occurred in 34 patients (90%) (Table 2) but none of the adverse events were grade 3 or higher. Two patients discontinued enzalutamide due to prolonged grade 1 or 2 fatigue but they are on ADT alone without evidence of disease progression. Eight patients (21%) demonstrated PSA response, and there was no radiologic response during enzalutamide therapy. PSA and/or radiologic progression was noted in 3 patients, thereby 93% were PSA progression-free at 12 months (Fig. 1).

DISCUSSION

The present study shows that maintenance therapy with enzalutamide is a feasible treatment option with potential therapeutic benefit for patients with high-volume mCNPC, progression-free following first-line docetaxel plus ADT. The finding is consistent with previous studies [6,7] in which the effect of enzalutamide for mCNPC was substantial regardless of early docetaxel treatment. Although the number of patients and follow-up duration are limited in the present study, baseline characteristics were generally consistent with those seen in these phase III studies, with the only exception that we included high-volume disease.
Although there are more than a few newly developed treatment options for mCNPC [5,8], it is not possible to replace ADT plus docetaxel, for high-volume disease in particular. It is suggested that the high tumor burden is a poor prognostic factor, and patients are suffering from symptoms of metastatic disease. The addition of docetaxel to ADT is often preferred in patients with mCNPC based on a high-volume of disease and potentially the symptomatic burden [13]. On the other hand, considering most cases are diagnosed in elderly patients, hematologic toxicities of docetaxel can be a major hurdle for general application to mCNPC. In general, the safety profile of ARTAs seems more tolerable than docetaxel [13], although a direct comparison has never been made. Another difference between docetaxel and other ARTAs is the treatment duration. Patients with mCNPC receive ADT plus either <6 months of docetaxel or long-term (i.e., until progression or unacceptable adverse events) ARTAs [3,5-7]. The omission of excessive docetaxel cycles may avoid unnecessary cumulative toxicity which may sometimes be severe. Conversely, the majority of patients will progress after the cessation of first-line therapy. In our prospective phase II study involving first-line docetaxel plus ADT in mCNPC patients [14], the median PFS was 26 months.
Despite major advancements in prostate cancer treatment, mCNPC remains an incurable condition where the aim of treatment is to improve survival and to palliate symptoms. In general, systemic therapy in mCNPC should be focused on prolongation of time to PSA progression, as well as preserving the quality of life of the patients. Most patients are elderly, and usually a frail population with multiple comorbidities and poor tolerance to cytotoxic chemotherapy. Switch maintenance therapy with an active and tolerable treatment regimen in a well-selected patient population may have a beneficial effect on quality of life, as a direct effect of the improvement in clinical outcome. The major limitation of this study is its retrospective, noncomparative design. Patients received maintenance enzalutamide following first-line docetaxel at the discretion of the treating medical oncologist. As a result, it may be that clinical judgment withheld the use of cytotoxic chemotherapy from patients at high risk of adverse events or those with poor performance status. The definition of high-volume disease was not well-defined but judged by treating physicians. In general, guidelines included the presence of extensive bone metastases and/or visceral disease as a predictor for poor prognosis [9,15]. Patients included men with newly diagnosed metastatic disease and a small proportion of patients with recurrent disease. It seems unlikely to look for statistically different results in patients with recurrent disease, as the estimates of the effect of docetaxel were consistent with that seen in the whole population in previous trials [3,4]. In addition, the small number of patients led to biases and lack of significance of some considerations that otherwise would probably provide more consistent results. These questions are currently being addressed in our prospective study (ClinicalTrials.gov, NCT06015321; CRIS.nih.go.kr, KCT0009086), which aims to assess treatment outcomes with enzalutamide first-line maintenance, following 6 to 8 cycles of ADT plus docetaxel.

CONCLUSIONS

In conclusion, our data provide the evidence of feasibility and tolerable safety of enzalutamide first-line maintenance in patients with high-volume mCNPC, who were progressionfree following ADT+docetaxel. The findings warrant further investigation and the prospective study is under way.

NOTES

Funding/Support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Research Ethics

The study protocol was approved by the Institutional Review Board of Samsung Medical Center (IRB No. 2023-07-103), and all patients provided a written informed consent prior to both starting docetaxel and switch to enzalutamide.

Conflicts of Interest

The authors have nothing to disclose.

Author Contribution

Conceptualization: SHL, SWC, SHP; Data curation: JHJ, WS, MK, HHS, HGJ, BCJ, SIS, SSJ, SHP; Formal analysis: SHL, SWC; Methodology: SHP; Project administration: SHP; Visualization: SWC, SHP; Writing - original draft: SHL, SWC; Writing - review & editing: All authors.

Fig. 1.
Kaplan-Meier curve for time to prostate-specific antigen (PSA) progression.
juo-244600040002f1.jpg
Table 1.
Baseline patient characteristics and outcome of first-line docetaxel (N=38)
Characteristic Value
Age (yr) 68 (46-82)
Gleason score 9 (7-10)
 7 or 8 18 (47)
 9 or 10 20 (53)
Prior treatment to primary tumor
 Prostatectomy 5 (13)
 Radiotherapy 2 (5)
PSA (ng/mL)
 Prior to ADT 222.0 (3.3-10,000.0)
 Prior to docetaxel 147.0 (0.2-4,580.0)
 Prior to enzalutamide 3.2 (0.01-258.0)
Performance status
 No symptoms 20 (53)
 Symptomatic 18 (47)
Metastatic sites
 Bone 35 (92)
 Lymph nodes 28 (74)
 Lung 8 (21)
 Liver 1 (3)
Treatment duration of first-line docetaxel (mo) 2.8 (2.7-5.0)

Values are presented as median (range) or number (%).

PSA, prostate-specific antigen; ADT, androgen deprivation therapy.

Table 2.
Maximum grade adverse events per patient
Adverse event Grade 1 Grade 2
Anemia 19 (50) 4 (11)
Fatigue 20 (53) 4 (11)
Pain 10 (26) 2 (8)
Nail changes 8 (21) 0 (0)
Sensory neuropathy 8 (21) 0 (0)
Anorexia 15 (40) 0 (0)
Nausea 4 (11) 0 (0)
Stomatitis 4 (11) 0 (0)
Edema 11 (29) 0 (0)
Urinary tract symptoms 16 (42) 1 (3)

Values are presented as number (%).

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