A Complete Response to Combined Immunotherapy in a Patient with an ATM plus SF3B1 Mutation and a Moderate Tumor Mutational Burden with a High-Grade Treatment-Emergent Neuroendocrine Prostate Cancer: Case Report and Review of the Literature

Prostate cancer is one of the most common cancers in men and a leading cause of cancer death globally. Despite treatment advancements, advanced prostate cancer, particularly in the castration-resistant state (mCRPC), often leads to poor outcomes. Treatment-emergent neuroendocrine prostate cancer (T-NEPC), an aggressive variant, tends to develop in advanced stages as a resistance mechanism, manifesting with visceral metastases and atypical progression indicators, including stable or unraised prostate-specific antigen (PSA) levels [1].

T-NEPC exhibits loss of androgen receptor signaling and gains neuroendocrine characteristics, rendering it less responsive to conventional therapies like hormone therapy and chemotherapy [1]. Patients with aggressive phenotypes or T-NEPC are typically given chemotherapy, including docetaxel, cabazitaxel, and platinum-based combinations. However, there is a lack of consensus on second-line treatments for T-NEPC, resulting in suboptimal outcomes. A study showed a modest 23.5% objective response rate to various second-line treatments in T-NEPC patients, with a PSA reduction of only 16.2%. However, it is important to note that PSA trends are not indicative of therapeutic benefit for these types of tumor. Initial therapy with platinum-based chemotherapy showed promise in half of the treated patients, but disease progression led to the cessation of second-line therapy in over three-quarters of cases [2]. While immunotherapy has revolutionized the treatment of several solid tumors, it has not found a significant role in prostate cancer management, except for a small subset with specific genetic alterations like microsatellite instability (MSI-High) or high tumor mutational burden (TMB), where Pembrolizumab has been approved [3]. The potential of immunotherapy in T-NEPC remains uncertain, with more research needed to evaluate its efficacy in this lethal cancer subtype.

In this article, we describe a patient with T-NEPC who had progressed during platinum-based chemotherapy (cabazitaxel + carboplatin), and had a complete response with only 4 cycles of Ipilimumab and Nivolumab (Ipi/nivo). An next-generation sequencing (NGS) analysis done in the pelvic mass showed alterations that could explain the favorable treatment outcome. This case highlights the potential of IO as a treatment option for selected T-NEPC patients who have failed conventional therapies and suggests that further investigation into the use of IO in T-NEPC is warranted but should be guided by companion genetic analysis to guide more tailored treatment choices.

A 76-year-old male presented with elevated PSA levels (28 U/mL) during routine health screening, leading to a diagnosis of Gleason 9 (5 + 4) adenocarcinoma acinar of the prostate. He underwent robotic prostatectomy (pT3N0) in March 2020. Six months later, he had a biochemical recurrence followed by a Gallium68 PSMA-PET that showed lymph nodal and bone disease. Combined hormonal therapy was started with monthly s.c degarelix and enzalutamide 160 mg PO daily later switched to apalutamide due to fatigue and cognitive symptoms.

After 20 months of combined androgen blockade, the patient reported intense back pain and difficulty walking. Imaging revealed pelvic nodes and new bone disease progression despite undetectable PSA levels. New lesions showed higher uptake in the FDG-PET and lower or no uptake in the PSMA-PET (shown in Fig. 1).

A percutaneous biopsy of the pelvic mass was performed, and final pathology was consistent with a T-NEPC (shown in Fig. 2). Immunohistochemistry showed diffuse AE1/AE3, chromogranin A, and synaptophysin positivity, and a Ki-67 proliferative index of 90%. Due to the appearance of neuroendocrine characteristics, chemotherapy combination with 6 cycles of cabazitaxel (20 mg/m²) and carboplatin (AUC 5.0) IV every 3 weeks plus G-CSF was started, as was SBRT for the spine bone lesion as well as monthly s.c. denosumab.

PSA levels remained undetectable, and despite chemotherapy, the pain persisted, and a new FDG-PET scan showed disease progression, and a PSMA-PET was negative for lesion uptake. The initial pathological staging of the tumor was deemed pT3N0 (AJCC/TNM 8a ed.), while the histological diagnosis obtained from the robotic prostatectomy revealed an adenocarcinoma acinar of the prostate, Gleason 9 (5 + 4), Group 5 (ISUP/OMS 2016).

A molecular test of the recent biopsy was sent for NGS at Foundation Medicine (Foundation^®CDx). Results showed the presence of an intermediary tumor burden (TMB: 9 Muts/Mb), absence of microsatellite instability, and ATM mutation (splice site 3077+1G>A and 8011-1G>A) and also a SF3B1 (G742D) mutation.

Due to the lack of response to standard options, the board decision and ethical exception approval were made to start a combination of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) (Ipi/nivo) IV every 3 weeks based on recent trials have shown the efficacy of using combination immunotherapy in rare high-grade neuroendocrine tumors with similar dose regimens [4]. Treatment provided a fast resolution of pain and improved quality of life until the 3rd cycle, when the patient started complaining of bilateral impairment of the peripheral visual fields, being initially diagnosed with rapidly progressing chorioretinal inflammation with serous retinal detachment. The fourth cycle of Ipi/nivo was administered without delay.

During ophthalmological examination, it was observed retinal alterations found after the 3rd cycle. In the ultra-wide field retinography done, it was possible to see that the patient developed a rare IRAE (Harada like syndrome) after IO for metastatic cancer with sunglow appearance.

Immunotherapy was suspended and the patient was started on prednisone (1 mg/kg) for 5 consecutive days, followed by dose reduction and then by intra-ocular applications of steroids. The decision to withhold immunotherapy and start the patient on prednisone was made to address the potential risk of permanent vision loss.

After the 4th cycle, a new FDG-PET was done and confirmed a complete metabolic response and a near complete radiological response. Despite the discontinuation of Ipi/nivo, the patient maintained a complete metabolic response on the follow-up PET-CT done after 3 and 6 months of therapy.

After 9 months of follow-up, he had a slight increase in PSA; new images found two retroperitoneal nodes. He returned to hormonal blockade and radiosurgery to the nodes. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540573).

Taking into account the novel systemic treatments and the evolving therapeutic landscape for prostate tumors, particularly in the context of aggressive variants like treatment-emergent neuroendocrine prostate cancer (T-NEPC), several critical facets emerge. In the last 20 years, the advent of new systemic therapies in advanced prostate cancer has been able to increase survival and quality of life of patients [5]. Unfortunately, traditional treatments, including androgen deprivation and chemotherapy, often show limited efficacy in advanced stages, prompting exploration of novel therapies with different mechanisms of action, like new androgen receptor signaling inhibitors, radionuclides, targeted therapies, as well as immunotherapy as potential breakthrough options to increase disease control and survival. While immune checkpoint inhibitors (IO) have revolutionized treatment for various cancers, their role in prostate cancer has been largely confined to specific genetic contexts such as microsatellite instability-high (MSI-H) tumors (only 3% of the cases) and those with TMB above 10 mut/Mb. However, T-NEPC presents a unique challenge due to its neuroendocrine differentiation and resistance mechanisms, necessitating innovative therapeutic approaches.

The focus of this case is T-NEPC treatment, which is an aggressive subtype often arising as a mechanism of treatment resistance in advanced prostate cancer, sometimes independent to PSA progression and related to the loss of androgen receptor dependence. This patient’s journey highlights the importance of considering immunotherapy for T-NEPC and leveraging genetic profiling for new biomarkers for IO response.

In recent years, IO like Ipi/nivo has shown remarkable efficacy changing the natural history of various cancers, and also as an agnostic therapy for tumors presenting with high tumor burden (>10 Muts/Mb) and MSI-high tumors [6]. However, exploration of these drugs in rare neoplasms remains limited.

The SWOG 1609/DART trial was a phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade, conducted to evaluate the efficacy of Ipi/nivo in a cohort constituted by refractory neuroendocrine neoplasms, with the exception of pancreatic neuroendocrine tumors. This therapy demonstrated a 44% objective response rate, irrespective of the organ of origin, including only 2 cases of prostatic primary site [4]. The positive findings served as rational for the administration of this dual blockade in our patient, after failing conventional treatments used for T-NEPC.

Initially, T-NEPC displays sensitivity to platinum-based chemotherapy, including combinations like platinum combined with etoposide or docetaxel, yielding an objective response rate ranging from 40 to 67%. Despite the initial positive response, the disease invariably advances within a brief period, resulting in a limited duration of response. The median progression-free survival (PFS) and overall survival (OS) are reported at 2–8 months and 8–19 months, respectively. However, both prospective and retrospective studies have demonstrated that the treatment outcome of second-line therapy using platinum with etoposide or docetaxel for T-NEPC is unfavorable, with a progression-free survival of 3 months or shorter [7].

Due to the lack of benefit of usual second-line therapies, new approaches have been investigated for T-NEPC, with several initial studies ongoing evaluating the benefit of IO in this scenario (Table 1). Unfortunately, even in tumors considered sensitive to immunotherapy, predicting treatment response rates is still a challenge and complete responses are exceeding low. A recent study explored the prognostic role of albumin levels as a more reliable potential prognostic biomarker іn ICI therapy, findings indicate that lower albumin levels correlate with poorer survival outcomes [8].

The search for biomarkers that will allow for a more individualized treatment based on genetic profile and tumor characteristics is essential. In our case, DNA analysis revealed a moderate TMB of 9 Muts/Mb, considered higher than encountered in the usual prostatic adenocarcinomas but not enough to justify immunotherapy use by international guidelines [9].

The definition of a high TMB, set at >10 Muts/Mb, remains somewhat arbitrary, yet it functions as a benchmark for the application of immunotherapy, although different boundaries have been studied in different tumor types. In this instance, even with a moderate TMB, the patient exhibited an exceptional response to the Ipi/nivo combination, prompting an exploration of additional contributing factors.

The genomic analysis unveiled a pathological ATM mutation. In prostate cancer, tumoral ATM mutations may be either germline or somatic in origin, and are present in 5–8% of castration-resistant tumors overall, an enrichment of approximately twofold over the frequency in localized prostate cancers. Beyond acting as a potential prognostic biomarker in prostate cancer, ATM status may also be predictive of response to novel targeted therapies. Initial trials of the PARP inhibitor, olaparib, in mCRPC showed an impressive response rate among patients with mutations in the homologous recombination repair pathway (HRD), apparently including patients with ATM deficiency [10].

Preliminary studies also suggest a potential sensitivity of ATM-mutated prostate cancers to anti-PD-1 immunotherapy. An analysis of independent prostate cancer cohorts indicated a statistically significant higher TMB in the ATM-altered group than the ATM-wild-type group, pointing toward promising immunotherapy opportunities in ATM-altered mCRPC [11].

Our patient presented with a very unique SF3B1 mutation (G742D). This mutation has been well characterized in CLL and other SF3B1 mutation (k700E), also very common in MDS. For solid tumors, only rare cases of breast cancer, pancreatic cancer and uveal melanoma were well described, but not for the G742D. All these hotspot mutations occur within highly conserved sequences, indicating their presence in functionally important regions [12]. The role of this mutation in tumorigenesis and its ability to dysregulate multiple cellular functions, including heme biosynthesis, immune infiltration and DNA damage response are also known. Additionally, it affects multiple cellular pathways, including mitochondrial, Notch, and NF-κB pathways [13].

In a recent preclinical investigation, cells with SF3B1 mutations exhibited heightened sensitivity to glycolysis inhibition compared to SF3B1 wild-type cells. Consequently, this research unveils a novel dimension of the oncogenic impact associated with mutant SF3B1 and proposes a promising therapeutic strategy centered on glycolysis inhibition [14]. It is possible that its effect in glycolysis had also contributed to the effect of IO observed, as preclinical studies are showing the relation between slope factor gene mutations like SF3B1 and a higher tumor burden and differences in CD4/CD8 expression.

Recent studies have revealed that tumor glycolysis induces T-cell exhaustion and enables immune escape. A study conducted with uveal melanoma stands out, as it elucidates the associations between glycolysis-related genes and uveal melanoma survival, thereby substantiating the prognostic significance of glycolysis in this context [15].

Another area of interest has linked SF3B1 mutations with sensitivity to ionizing radiation, chemotherapy agents and specially PARP inhibitors, with a similarity to BRCA mutated cancers [16]. Finally, studies have shown that SF3B1 as well as other splice factor genes are related to high tumor burden as well as changes in tumor microenvironment (TME) that could lead to a better response to IO therapies [17].

The pivotal role played by Ipi/nivo in treating T-NEPC cases becomes evident. The intricacies of the TME and microbiome, recognized as influential factors in tumor resistance or response to therapies, further underscore the multifaceted nature of the situation. Emerging evidence indicates that the gut microbiome can influence the development of cancer, the tumor microenvironment as well as the response to anticancer treatments such as chemotherapy, targeted therapies, ADT, and immunotherapy [18]. Recent findings on the role of microbiome in cancer were summarized by Zhao and cols [19]. The initial clues on molecular mechanisms regarding the mutual effects between the gut microbiota and cancer development, and the relationship between gut microbes and the efficacy of immunotherapy, chemotherapy, radiation, and cancer surgery, are important insights into the formulation of individualized strategies for cancer management [18, 19].

In spite of the advances made with ICIs, it is important to highlight possible adverse events induced by this new therapy, such as the rare ophthalmological event that occurred in our case, that led to treatment interruption [20]. Despite the challenges, this case serves as a reminder of the paramount importance of research, personalized treatment approaches, and innovative therapies in effectively managing T-NEPC, but also opens the possibility to explore additional biomarkers for IO response.

In addition to the clinical discussion, we conducted a comprehensive review of the existing literature on the treatment of T-NEPC. These tables synthesized information on ongoing treatment modalities, including traditional approaches and emerging strategies with immunotherapy (Tables 1, 2) to further understand the available resources for the treatment of these patients.

This case underscores the critical need for continued and vigorous research on biomarkers to enhance the efficacy of immunotherapeutic strategies, particularly in the management of aggressive cancer subtypes like t-NEPC. It also highlights the potential significance of immunotherapy in patients with specific combined mutations such as ATM and SF3B1.

This study protocol was reviewed and the need for approval was waived by our local IRB, Comitê de Ética em Pesquisa do Instituto D’Or de Pesquisa e Ensino (IDOR). Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Within the documentation, the patient has provided approval for the inclusion of their images and related clinical details in the journal. The patient acknowledges that their identities, including names and initials, will remain confidential, and sincere attempts will be made to safeguard their anonymity.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

H.F.B. designed and drafted the paper, analyzed and interpreted the patient data. G.C.K.L. and H.B.V.B. interpreted the patient data and also participated in the draft of the work. S.A.A. analyzed the patients’ imaging exams, F.A. performed the histological examination of the tumor biopsy, and E.L. provided detailed analysis of the patients’ ophthalmologic adverse effects. They were a major contributor in writing the manuscript. S.P.P., V.F., and D.H. thoughtfully revised the work. D.H. also participated in the design and drafting. All authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.