Clinical response to novel combination of trastuzumab deruxtecan and abiraterone in HER2-expressing metastatic castration-resistant prostate cancer

Abstract

Human Epidermal Growth Factor Receptor 2 (HER2) is expressed in approximately 60%-70% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may contribute to androgen resistance. This case report describes a patient with HER2-expressing mCRPC who progressed on multiple lines of therapy and subsequently had a significant response to combination treatment with the HER2-targeting antibody-drug-conjugate (ADC) trastuzumab deruxtecan (T-DXd) and re-­challenge of abiraterone, despite having progressed on this prior. Unlike other HER2-expressing malignancies, HER2 overexpression in prostate cancer (PCa) occurs in the absence of HER2 mutations and amplifications and, as such, is not detected by next-­generation sequencing. Therefore, identifying patients with mCRPC who could benefit from T-DXd necessitates HER2 testing by immunohistochemistry (IHC), a practice not routinely performed. As a result, T-DXd remains underutilized in patients with mCRPC, despite a tumor-agnostic approval for patients with advanced HER2-expressing (IHC 3+) solid tumors. This case highlights the potential of combining T-DXd with androgen receptor pathway inhibitors to overcome treatment resistance and underscores the importance of routine HER2 IHC testing in patients with advanced PCa.

Key Points.

• Human Epidermal Growth Factor Receptor 2 (HER2) is expressed in approximately 60%-70% of patients with metastatic castration-resistant prostate cancer (mCRPC) representing a therapeutic target that could respond to HER2-targeting antibody-drug conjugates (ADC), such as trastuzumab deruxtecan (T-DXd). Despite the pan-tumor approval of T-DXd in advanced HER2-positive (IHC 3+) solid tumors, the role of T-DXd in mCRPC remains underexplored, as major trials like DESTINY-PanTumor02 did not include patients with prostate cancer (PCa).

• HER2 alterations, including amplifications or mutations, are rarely present in mCRPC and, as such, are not detected by next-generation sequencing. As a result, HER2-overexpression in PCa is often missed in clinical practice because IHC testing is not routinely performed. HER2 IHC testing should be considered in mCRPC as it may identify a subset of patients who could benefit from T-DXd.

• We report a case of a 64-year-old male with HER2-expressing mCRPC and extensive liver metastases, demonstrating a remarkable response to combination treatment of T-DXd and re-challenge of abiraterone. This suggests that T-DXd may help overcome androgen resistance, warranting further evaluation in follow-up studies.

Introduction

Androgen-deprivation therapy (ADT) impedes androgen receptor (AR) signaling in prostate cancer (PCa) and serves as the mainstay of treatment. Novel androgen receptor pathway inhibitors (ARPI), such as abiraterone and enzalutamide, can further block persistent androgen signaling, which has resulted in substantially increased survival rates for patients with metastatic castration-resistant prostate cancer (mCRPC). Nonetheless, despite initial therapeutic effect almost all patients eventually progress as a result of androgen-independent growth. Emerging evidence suggests that human epidermal growth factor receptor 2 (HER2) expression in PCa is associated with lower levels of AR expression, allowing these tumor cells to escape AR dependence, contributing to disease progression.^1–4 As such, HER2 could represent a therapeutic target to overcome treatment resistance.^5,6 HER2 is expressed in approximately 60%-70% of patients with mCRPC, though rarely detected, as immunohistochemistry (IHC) is not routinely performed in current clinical practice.^4–7 Here, we describe a patient with HER2-­expressing mCRPC with a remarkable response to trastuzumab deruxtecan (T-DXd) and re-challenge of abiraterone. This report adds to the body of evidence on the efficacy and safety of T-DXd in mCRPC, as the DESTINY- PanTumor02 trial and other prior trials did not include patients with PCa.⁸

Patient story

A 64-year-old male was diagnosed with de novo metastatic PCa in 2015 after work-up of metastatic disease revealed a prostate-specific antigen (PSA) level of >11 000 ng/mL and a bone biopsy confirmed prostate adenocarcinoma. Molecular testing revealed CDK12 loss (p.K804*) and low tumor mutational burden. He was started on ADT with leuprolide in combination with docetaxel and achieved a clinical remission after 6 cycles. Within 2 months, the patient progressed despite achieving castrate testosterone levels. Over the next 8 years, he was treated with 6 consecutive lines of treatment (sipuleucel-T, abiraterone, re-challenge docetaxel, cabazitaxel plus carboplatin, lutetium-117(¹⁷⁷Lu)-PSMA-617, and olaparib). However, the response to each of these therapies was short-lived, and the patient demonstrated transient decreases in PSA levels, quickly followed by biochemical recurrence. Colonoscopy performed in April 2024 for hematochezia and worsening pelvic pain revealed a rectal mass with biopsies confirming metastatic PCa. Repeat molecular studies revealed the previously observed loss of CDK12 (p.K804*) as well as new loss of PTEN (p.E256*) and mutated TP53 (p.V216M), but no actionable alterations. He subsequently received 5 rounds of palliative radiation to the pelvis. Follow-up imaging subsequently demonstrated new liver metastatic disease. As part of a clinical trial, he received 3 cycles of pembrolizumab (CHOMP; NCT 04104893) which was discontinued due to disease progression and was started on enzalutamide. However, PSA continued to rise, and the patient reported worsening fatigue, pelvic pain, and difficulty with ambulating. Imaging performed in August 2024 showed worsening visceral metastatic disease, including bulky lymphadenopathy, and extensive liver and rectal metastases (Figure 1). PSA level was found to be greater than 5000 ng/mL. In the absence of treatment options, IHC for HER2 was performed on the rectal metastasis, revealing strong (3+) expression using our previously published PCa-specific scoring schema (Figure 2).^6,9 Treatment with T-DXd was initiated in September 2024. However, in October 2024, after receiving one cycle of T-DXd, imaging revealed further progression (Figure 1). Due to declining performance status, worsening liver function tests, and an anticipated prognosis of less than three months, abiraterone was re-trialed in combination with T-DXd, despite the disease having previously progressed on both abiraterone and enzalutamide. Remarkably, after 4 cycles of combination T-DXd and abiraterone, his condition significantly improved. He reported subjective improvement in energy, exercise tolerance, and appetite, and he demonstrated a 15-pound weight gain since the start of the combination therapy. Although his PSA level continued to be greater than 5000 ng/mL, he showed notable improvement in liver function parameters (reduction in alkaline phosphatase from 1576 U/L to 340 U/L and normalization of transaminases). Moreover, imaging after 6 cycles of combination therapy in January 2025 showed a 70.5% overall reduction in tumor volume across visceral metastatic sites, including a 52% interval reduction in tumor volume in the dominant liver lesion, as well as stable osseous lesions compared to October 2024 (Figure 1).

Figure 1.

Computed tomography (CT) imaging of tumor response to T-DXd and abiraterone. (A–C) Axial contrast-enhanced CT image of the abdomen before treatment with T-DXd (A), after 1 cycle of treatment with T-DXd (B), and after 6 cycles of treatment with T-DXd and abiraterone (C). The dominant liver lesion (red arrow) measures 9 × 8 × 6 cm in (A), 14 × 13 × 10 cm in (B) and 10 × 10 × 9 cm in (C), demonstrating a 52% interval reduction in tumor volume between (B) and (C). (D–F) Axial contrast-enhanced CT image of the abdomen before treatment with T-DXd (D), after 1 cycle of treatment with T-DXd (E) and after 6 cycles of treatment with T-DXd and abiraterone (F). The enlarged portocaval lymph node (yellow arrow) measures 3 × 3 × 2 cm in (D), 4 × 4 × 3 cm in (E). and 3 × 3 × 2 cm in (F), demonstrating a 68% interval reduction in tumor volume between (E) and (F). (G–I) Axial contrast-­enhanced CT image of the pelvis before treatment with T-DXd (G), after 1 cycle of treatment with T-DXd (H), and after 6 cycles of treatment with T-DXd and abiraterone (I). The enlarged pelvic lymph node (green arrow) measures in 6 × 4 × 4 cm in (G), 8 × 5 × 2 cm in (H) and 3 × 2 × 1 cm in (I), demonstrating a 92% interval reduction in tumor volume between (H) and (I).

Figure 2.

Histopathology of metastatic prostate adenocarcinoma involving rectum. (A) Representative micrograph of the rectal lesion (Hematoxylin & Eosin stain) showing fragments of viable poorly differentiated prostate adenocarcinoma (tumor cells positive for NKX3.1, not shown) (red arrows), colonic mucosa (green arrow), and areas of necrosis (yellow arrow). (B) IHC for HER2 shows focal strong (3+) expression in prostate adenocarcinoma (red arrows) based on a modified scoring system from our institution (reference 3 for details). HER2 expression is negative on colonic mucosa (green arrow). All images at 100× magnification.

Molecular tumor board

The development of mCRPC and ADT failure are closely related to the dynamics of AR activity. While ADT is initially successful in inhibiting tumor proliferation by suppressing AR signaling, resistance can arise through various mechanisms involving AR or alternative signaling pathways.¹⁰ Sustained AR activity in the setting of castrate testosterone levels may occur through several mechanisms, such as AR amplification, mutations, and the development of AR splice variants.^10,11 Alternative pathways, such as Wnt/β-catenin and neuregulin 1/HER2/HER3, may bypass AR signaling, and can contribute to sustained downstream effects resulting in tumor proliferation and survival, even in the absence of AR activity.^12,13 Studies have suggested an inverse relationship between AR and HER2 signaling in PCa.^1–4 This finding emphasizes that as AR activity is diminished, HER2 may become more prominent in driving tumor proliferation. Unlike other HER2-expressing malignancies, expression of HER2 in PCa occurs in the absence of HER2 alterations and, therefore, is not detected by next-generation sequencing.^6,13 The notable response to T-DXd observed in this case, as well as in a previously reported case report of neuroendocrine PCa, underscores the importance of testing HER2 expression by IHC in patients with advanced PCa to identify those who may benefit from T-DXd.⁹

Additionally, we show that combining T-DXd with an ARPI is safe and could be an effective therapeutic strategy, potentially overcoming androgen resistance in mCRPC. Our prior report was the first published case of a patient with mCRPC responding to T-DXd after disease progression on multiple lines of therapy, including abiraterone.⁹ This patient was treated with T-DXd starting February 2024 and abiraterone was added in September 2024 due to progression of disease including worsening lymphadenopathy and rapid growth of a dural-based mass. Prostate-specific antigen had trended up at that time to 92 ng/mL. He symptomatically improved, PSA trended down to 53.9 ng/mL, and imaging obtained in January 2025 revealed stable disease. After 14 months of treatment with either T-DXd alone or in combination with abiraterone, his disease progressed in April 2025, and this treatment was discontinued. Both cases highlight the potential of combining T-DXd and re-challenging with an ARPI for the treatment of mCRPC. In clinical practice, once a patient with mCRPC fails an ARPI, providers can switch to another one with a different mechanism of action. Patients are not administered the same ARPI again because of a lack of clinical response. The safety of trastuzumab combined with an ARPI has been previously reported in a clinical trial involving patients with HER2-positive and AR-positive breast cancer.¹⁴ Although the underlying mechanism for this potential synergistic effect in PCa is not clear, HER2-inhibition may target a subpopulation of HER2-positive/AR-low tumor cells that could have evaded the effect of ADT, resulting in clinical resensitization to androgen inhibition as a result of enrichment of clonal AR expression.⁴ The interplay of AR with other signaling pathways shows the potential for an integrated approach to overcome ADT resistance.

Prostate cancer liver metastasis (PCLM) remains the most lethal site of mCRPC with a median overall survival of 10 to 14 months.^15,16 Despite reports of an increasing incidence of PCLM in around 25% of patients with mCRPC, therapeutic options are limited as it does not seem to respond to conventional therapies for mCRPC, such as ARPI or chemotherapy.^15–17 Literature suggests that exposure to multiple lines of treatments, namely ARPI and taxanes, may be a risk factor for increased incidence of visceral metastases in mCRPC, though an independent association has not yet been demonstrated.¹⁸ It is hypothesized that a combination of treatment-induced chronic liver injury and a higher incidence of genomic alterations in PCLM compared to other visceral metastatic sites may predispose toward a more aggressive clinical course in these patients.^15,16 The patient in this report was initially diagnosed with liver metastases in April 2024 associated with a rapid increase in serum biomarkers and clinical deterioration. However, despite having previously failed multiple lines of therapy and a gap in treatment of 6 weeks, the patient’s response to combination T-DXd and abiraterone and survival after 1 year of diagnosis of PCLM as of April 2025 exceeds expectations for this stage of disease.

While our findings suggest that combining T-DXd with an ARPI may offer therapeutic benefit for patients with HER2-­expressing mCRPC, this conclusion is based on limited data. Considering the high incidence of ADT failure, further research is necessary to determine whether T-DXd can overcome resistance to treatment. An ongoing clinical trial (NCT06610825), opened for enrollment in March 2025, will evaluate response to T-DXd in patients with HER2-expressing mCRPC.

Patient update

As of April 2025, this heavily pre-treated patient with extensive systemic metastases continues to demonstrate symptomatic improvement, and his functional status has markedly improved from being bed-ridden to walking 1 mile per day at home. Follow-up imaging 6 months after starting treatment with T-DXd demonstrate stable lymph node and bone metastases, and progression in the liver metastatic lesions.

Funding

This work was supported by the Prostate Cancer Foundation (PCF) [grant number: 19VALO01].

Conflicts of interest

The authors declare no financial conflicts of interest with this manuscript.

Data availability

The data underlying this article are available in the article.

Ethics statement

Approval of the research protocol by an Institutional Review Board: Institutional Review Board approval was waived for this case report in accordance with institutional guidelines. Informed consent: The authors declare that they have the express consent form signed by the patient for the publication of the case. Registry and the registration number of the study/trial: N/A. Animal studies: N/A.