Complete Response to Concurrent Triplet Therapy in Low‐Volume Metastatic Hormone‐Sensitive Prostate Cancer: A Case Report

ABSTRACT

Introduction

Triplet therapy with androgen deprivation therapy (ADT), an androgen receptor pathway inhibitor, and docetaxel improves survival in metastatic hormone‐sensitive prostate cancer (mHSPC), but its role in low‐volume disease remains unclear.

Case Presentation

A 68‐year‐old man presented with dysuria and a PSA increase to 34.49 ng/mL. Imaging revealed a prostate tumor extending into the bladder, right obturator lymph node metastasis, and a bone lesion. Biopsy showed Gleason score 5 + 5 prostate adenocarcinoma (cT4N1M1b low‐volume mHSPC). Concurrent triplet therapy with ADT, darolutamide, and docetaxel was initiated. PSA decreased to 0.1 ng/mL within 2 months, and imaging at 4.5 months demonstrated a radiological complete response. At the latest follow‐up (7 months), the PSA remained below 0.03 ng/mL without progression to CRPC.

Conclusion

Concurrent triplet therapy may achieve complete response in selected patients with aggressive low‐volume mHSPC.

Key Message

Concurrent triplet therapy may induce a complete response in selected patients with biologically aggressive low‐volume metastatic hormone‐sensitive prostate cancer.

1. Introduction

Triplet therapy consisting of androgen deprivation therapy (ADT), an androgen receptor pathway inhibitor (ARPI), and docetaxel has demonstrated a survival benefit in patients with metastatic hormone‐sensitive prostate cancer (mHSPC) [1, 2], particularly in those with high‐volume disease. However, its role in low‐volume mHSPC remains controversial, as subgroup analyses have not consistently shown a clear survival benefit in this population [3].

Although low‐volume disease is generally considered to have a more favorable prognosis, some patients exhibit aggressive clinical features regardless of metastatic burden. In particular, locally advanced tumors and high‐grade disease may be associated with poor outcomes even in low‐volume cases.

Furthermore, recent evidence suggests that the timing of treatment initiation may influence therapeutic outcomes.

Herein, we report a case of biologically aggressive low‐volume mHSPC that achieved a radiological complete response following concurrent triplet therapy.

2. Case Presentation

A 68‐year‐old man presented with dysuria and was referred to our hospital. He had undergone photoselective vaporization of the prostate for benign prostatic hyperplasia 18 months earlier, at which time his prostate‐specific antigen (PSA) level was 2.91 ng/mL. At presentation, his PSA level had increased to 34.49 ng/mL. His performance status was 1.

Pelvic magnetic resonance imaging revealed a tumor extending from the prostate into the bladder, suggesting locally advanced disease. A lesion suspicious for bone metastasis was identified in the right ischium on pelvic MRI, and corresponding abnormal uptake was confirmed by bone scintigraphy (Figure 1). Contrast‐enhanced computed tomography demonstrated right obturator lymph node metastasis and left hydronephrosis (Figure 2). Transurethral biopsy revealed prostate adenocarcinoma with a Gleason score of 5 + 5. Based on these findings, the patient was diagnosed with cT4N1M1b prostate cancer. According to the CHAARTED criteria, the disease was classified as low‐volume.

FIGURE 1.

Magnetic resonance imaging findings at diagnosis. Axial T2‐weighted magnetic resonance imaging demonstrates a prostate tumor extending into the bladder, indicating locally advanced disease. A lesion suspicious for bone metastasis is also observed in the right ischium (arrowhead).

FIGURE 2.

Contrast‐enhanced computed tomography findings at diagnosis. Computed tomography shows right obturator lymph node metastasis (arrowhead) and left hydronephrosis (arrowhead), suggesting locally advanced disease with nodal involvement and urinary tract obstruction.

Before chemotherapy, renal function was impaired due to hydronephrosis (serum creatinine: 1.49 mg/dL; estimated glomerular filtration rate [eGFR]: 37.36 mL/min/1.73 m²).

Considering the aggressive pathological features, including Gleason score 10 and locally advanced disease (cT4), androgen deprivation therapy with a luteinizing hormone‐releasing hormone agonist, darolutamide, and docetaxel was initiated on the same day. Docetaxel was administered at a dose of 70 mg/m² every 3 weeks for six cycles and was completed without dose reduction. Primary prophylaxis with granulocyte colony‐stimulating factor was administered, and no febrile neutropenia occurred during treatment. No hepatic dysfunction was observed during treatment.

The PSA level rapidly declined to 0.1 ng/mL within 2 months after treatment initiation (Figure 3). Hydronephrosis improved with treatment, and renal function recovered (serum creatinine: 1.02 mg/dL; eGFR: 56.55 mL/min/1.73 m²). Follow‐up pelvic magnetic resonance imaging and noncontrast computed tomography performed 4.5 months after treatment initiation demonstrated complete resolution of the primary prostate lesion, right obturator lymph node metastasis, and right ischial bone lesion, indicating a radiological complete response (Figure 4). At the latest follow‐up, 7 months after treatment initiation, the patient remains on ADT plus darolutamide without evidence of disease progression. The PSA level has remained below 0.03 ng/mL, representing the PSA nadir, and no progression to castration‐resistant prostate cancer has been observed.

FIGURE 3.

Changes in prostate‐specific antigen (PSA) levels during treatment. The PSA level rapidly decreased following initiation of concurrent triplet therapy, reaching 0.1 ng/mL within 2 months.

FIGURE 4.

Radiological response after treatment. Follow‐up pelvic magnetic resonance imaging and noncontrast computed tomography performed 4.5 months after treatment initiation demonstrated complete resolution of the primary prostate lesion, right obturator lymph node metastasis, and right ischial bone lesion, indicating a radiological complete response.

3. Discussion

Triplet therapy has demonstrated a survival benefit in patients with metastatic hormone‐sensitive prostate cancer (mHSPC), as shown in the ARASENS trial [1]. However, its role in low‐volume disease remains controversial. In a subgroup analysis of ARASENS, no statistically significant overall survival benefit was observed in patients with low‐volume disease (hazard ratio 0.68; 95% confidence interval crossed 1) [3].

Prostate cancer is a biologically heterogeneous disease in which androgen‐sensitive and androgen‐insensitive tumor cell populations are thought to coexist. This heterogeneity provides a rationale for early combination therapy targeting multiple oncogenic pathways [4]. Furthermore, low‐volume disease does not necessarily indicate a favorable prognosis. Previous studies have reported that patients with low‐volume disease and cT4 stage have outcomes comparable to those with high‐volume disease and cT3 stage [5]. These findings suggest that treatment intensification should be considered even in low‐volume mHSPC when aggressive clinical features such as cT4 stage are present.

In Japan, triplet therapy using darolutamide is based on the ARASENS protocol [1], in which darolutamide is initiated within 12 weeks of androgen deprivation therapy (ADT), and docetaxel is administered within 6 weeks thereafter, allowing some flexibility in treatment timing.

Emerging evidence suggests that the timing of treatment initiation may influence therapeutic outcomes. Administration of ADT and docetaxel within 2.2 months has been associated with improved progression‐free survival compared with longer intervals [6]. Additionally, based on the hypothesis that docetaxel may exert greater cytotoxic effects during the early phase following luteinizing hormone‐releasing hormone (LHRH) agonist administration, a subgroup analysis of the CHAARTED trial suggested that administration of docetaxel within 6 days of LHRH agonist initiation may be associated with a prolonged time to castration‐resistant prostate cancer [7]. Furthermore, shorter intervals between androgen receptor pathway inhibitors and docetaxel have been associated with greater tumor reduction [8].

Based on these findings, we adopted a concurrent administration strategy using a luteinizing hormone‐releasing hormone (LHRH) agonist, in combination with darolutamide and docetaxel, to maximize the therapeutic efficacy of triplet therapy.

Safety is also an important consideration. In the ARASENS trial, grade ≥ 3 neutropenia and febrile neutropenia were reported in 33.7% and 7.8% of patients, respectively [1]. At our institution, androgen deprivation therapy (ADT), darolutamide, and docetaxel are initiated simultaneously on the same day. Consequently, docetaxel is administered before castrate levels of testosterone are achieved. Previous pharmacokinetic studies have demonstrated that noncastrated patients have lower docetaxel clearance and greater systemic exposure than castrated patients, potentially increasing the risk of severe neutropenia [9]. Furthermore, real‐world data have shown that initiating docetaxel within 3 weeks after starting ADT is associated with a significantly higher incidence of febrile neutropenia [10]. Febrile neutropenia occurs most frequently during the first cycle of chemotherapy [11], and the relative dose intensity of docetaxel has been shown to impact prognosis [12]. Therefore, to reduce the risk of febrile neutropenia while maintaining treatment continuity and relative dose intensity, we administered docetaxel at an initial dose of 70 mg/m² together with primary prophylactic granulocyte colony‐stimulating factor. The patient completed all six cycles without febrile neutropenia or further dose reduction. Although the follow‐up period remains relatively short, the patient has maintained a PSA level below 0.03 ng/mL for 7 months after treatment initiation while continuing ADT plus darolutamide, without evidence of progression to castration‐resistant prostate cancer. A post hoc analysis of the ARASENS trial demonstrated that achieving a PSA level < 0.2 ng/mL was associated with improved overall survival, even in patients with low‐volume disease [13]. Although no statistically significant overall survival benefit of triplet therapy was observed in the low‐volume subgroup, this finding suggests that a deep PSA response may serve as a prognostic indicator in this population. The sustained deep PSA response observed in our patient further supports the potential durability and clinical significance of the initial therapeutic response. This case supports the use of concurrent triplet therapy in selected patients with biologically aggressive low‐volume mHSPC. Patients with adverse clinicopathological features, such as cT4 stage, Gleason score 9–10 disease, or other findings suggestive of aggressive tumor biology despite low metastatic burden, may be appropriate candidates for treatment intensification.

4. Conclusion

Concurrent triplet therapy may induce a complete response in selected patients with biologically aggressive low‐volume mHSPC.

Disclosure

The authors have nothing to report.

Ethics Statement

Approval of the research protocol by an institutional review board: Not applicable; this single‐patient case report is exempt under our institutional policy.

Consent

Written informed consent for publication, including images, was obtained from the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.