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Neuroendocrine Prostate Cancer…A Potential Role for Pembrolizumab and Other Newer Therapeutics?

Neuroendocrine prostate cancer (NEPC), as defined in the literature, is a heterogeneous group of cancers. The classic de novo small cell carcinoma of the prostate is quite rare, and what we typically see more often is treatment emergent NEPC. The common use of androgen receptor (AR) pathway inhibitors has led to adaptive escape mechanisms through lineage plasticity.1 Loss of AR expression and downstream signaling is occurring in approximately 20% of castration-resistant prostate cancers.2 As a result, we are seeing more metastatic castration-resistant prostate cancers reclassified as treatment-emergent NEPC.3

Some of these tumors may exhibit small cell morphology, although that is less common, as the trials have used various criteria to define NEPC. It is typical to see low AR expression and positive chromogranin and synaptophysin immunostaining, although INSM1 is another immunohistochemical marker with sensitive detection of neuroendocrine carcinoma.4 Some groups have used a mix of immunohistochemical and clinical features to define what was initially termed “anaplastic” but now may be more frequently termed an aggressive variant of prostate cancer.5 Others have used more molecular definitions, recognizing that tumor suppressor genes, such as pTEN, TP53, and most convincingly, Rb loss, have important roles in facilitating neuroendocrine differentiation.6,7 It is important to recognize that most trials that report on prognosis, treatment efficacy, and outcomes of NEPC are comprised of a heterogeneous group of patients, many of whom do not have classic small cell carcinoma.

For a lack of better therapeutic agents, first-line treatment for NEPC generally includes platinum combination chemotherapy. Given rapid relapses after platinum chemotherapy, salvage treatment options are limited, with poor response rates. Many providers have extrapolated from the small cell lung carcinoma FDA approvals of atezolizumab8 and lurbinectedin;9 however, these approvals do not formally extend to NEPC, and they are not recommended in national guidelines.

Newer targets, such as Delta-like ligand 3 (DLL3), are highly expressed on NEPC.10 There has been some excitement surrounding the regulatory approval of tarlatamab, a bispecific T-cell engager that redirects T cells to kill DLL3-expressing tumors.11 Although this is again for small cell carcinoma of the lung, there is early data from the Phase 1b (DeLLpro-300) trial, which enrolled subjects with either de novo or treatment-emergent neuroendocrine prostate cancer (NCT04702737). Although the objective response rates were only 10.5%, patients whose tumors expressed >1% DLL3 tumor positivity had a 22.2% response rate.12

Most recently, at the ASCO 2025 Annual Meeting, preliminary results from Cohort I of the KEYNOTE-365 (NCT02861573) were presented. This cohort evaluated the addition of pembrolizumab to carboplatin and etoposide for true morphologic small cell, large cell, or mixed NEPC, using central pathology review requiring confirmation of diagnosis and eligibility by three separate pathologists. The confirmed objective response rates, by Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR, were 33% (8/24) for pembrolizumab plus carboplatin and etoposide vs. 10% (2/21) for carboplatin and etoposide alone.13 These response rates are worse than expected, especially for the patients in the standard of care control arm; however, this is likely due to the stringent eligibility criteria, mandatory morphological small cell, large cell, or mixed NEPC. Radiographic progression-free survival was 5.1 (4.1-8.0) vs. 4.0 (2.1-5.0) months (HR 0.51 [95% CI 0.23-1.11]) for pembrolizumab plus carboplatin and etoposide vs. carboplatin and etoposide, respectively. Overall survival was 10.3 (8.0-13.2) vs. 7.8 (4.0-8.5) months (HR 0.28 [95% CI 0.12-0.65]) for pembrolizumab plus carboplatin and etoposide vs. carboplatin and etoposide, respectively.

Although the above trial is still actively accruing patients, the potential improvement in overall survival in the NEPC patient population receiving pembrolizumab should pique interest in the field. After the FDA approval of atezolizumab for small cell lung carcinoma, the NCCN guidelines initially referenced consideration of use for NEPC. The next year, this was removed, and we have not seen further endorsement of checkpoint inhibitor therapy. The KEYNOTE-365 trial should complete accrual and present final results. If the final data is impressive, then additional consideration should be given to the topic of guideline recommendation, if not regulatory approval. This is especially important since there have not been any agents regulatory approved for NEPC.

Below, I list some active trials for patients with NEPC. These include chemotherapies, immunotherapies, radioligand therapies, tyrosine kinase inhibitors, and other novel therapeutics. These trials span various targets and offer unique mechanisms of action for this heterogeneous group of patients harboring an unmet clinical need.

Ongoing clinical trials for NEPC:

  • KEYNOTE-365 – Randomized Phase 1b of carboplatin and etoposide with or without pembrolizumab (NCT02861573)
  • CHAMP – Phase 2 trial of nivolumab, ipilumumab, cabazitaxel and carboplatin for aggressive variant or NEPC (NCT04709276)
  • Phase 2 trial of Nivolumab plus ipilumumab plus cabozantinib for rare genitourinary tumors, including NEPC (NCT03866382)
  • SKYBRIDGE – Phase 1 trial of PT217 bispecific antibody against DLL3/CD47, including NEPC (NCT05652686)
  • DeLLight – Tarlatamab for advanced extrapulmonary small cell, including NEPC (NCT06893783)
  • Phase 2 trial of ZG006, a trispecific T cell engager targeting DLL3/CD3, for metastatic NEPC (NCT07024277)
  • Phase 1/2 trial of HPN328, a trispecific T cell engager targeting DLL3/CD3, monotherapy and with atezolizumab in patients with neuroendocrine lung, prostate, and other neuroendocrine carcinomas (NCT04471727)
  • Phase 1 trial of 177Lu-DTPA-SC16.56 targeting DLL3 for NEPC and neuroendocrine carcinoma of lung (NCT06941480)
  • Phase 1 trial of 225Ac-ETN029 in patients with advanced DLL3-expressing solid tumors, including NEPC (NCT07006727)
  • Phase 2 trial of 177Lu-DOTA-TATE for NEPC (NCT05691465)
  • Phase 1 trial of 177Lu-PSMA-617, 177Lu-DOTA-TATE, or 177Lu-NeoB to target PSMA, SSTR2, or GRPR, respectively for metastatic NEPC (NCT06379217)
  • Phase 2 trial of ESK981, a multi-kinase and PIKfyve inhibitor, for select solid tumors, including NEPC (NCT05988918)
  • Phase 1/2 trial of JBI-802, an LSD1/HDAC6 inhibitor in advanced solid tumors, including NEPC (NCT05268666)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Beltran H, et al. The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance. Clin Cancer Res 2019; 25:6916-24.
  2. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501:328-37.
  3. Aggarwal R, et al. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol 2018; 36:2492-503.
  4. Moller K, et al. Comparison of INSM1 immunostaining with established neuroendocrine markers synaptophysin and chromogranin A in over 14,000 neuroendocrine and non-neuroendocrine tumors. Mol Cell Endocrinol 2024; 581:112106.
  5. Aparicio A, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res 2013; 19:3621-30.
  6. Labrecque MP, et al. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells. Oncotarget 2016; 7:24284-302.
  7. Tan HL, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res 2014; 20:890-903.
  8. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancerTan HL et al. Clin Cancer Res 2014; 20:890-903.
  9. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer
  10. Puca L, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med 2019; 11(484):eaav0891.
  11. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
  12. Aggarwal RR, et al. Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol 42, 2024 (suppl 16, abstr 5012).
  13. von Amsberg G, et al. Phase 1b/2 KEYNOTE-365 cohort I: Pembrolizumab (pembro) plus carboplatin and etoposide chemotherapy (chemo) or chemo alone for metastatic neuroendocrine prostate cancer (NEPC). J Clin Oncol 43, 2025 (suppl 16; abstr 5059).