Case Report: Deep and durable response to talazoparib in germline BRCA2-mutated rectal neuroendocrine carcinoma

Abstract

High-grade neuroendocrine carcinoma (NEC) of the rectum is a rare and aggressive malignancy, with limited treatment options and a poor prognosis. We report the successful off-label use of the PARP inhibitor talazoparib in a patient with metastatic, germline BRCA2-mutated rectal NEC who had a contraindication to standard immunotherapy due to underlying autoimmune disease. A 55-year-old man with ongoing severe psoriatic arthritis presented with a two-week history of rectal pain, abdominal distention, and diarrhea. Cross-sectional imaging demonstrated a rectal mass with mesorectal lymphadenopathy and multiple liver metastases. Biopsy of the rectal lesion demonstrated a high-grade, poorly differentiated NEC with a Ki-67 proliferation index of 99%. Comprehensive tumor molecular profiling identified a pathogenic BRCA2 mutation (c.5291C>G; p.Ser1764*, with loss of the wild-type allele), which was confirmed to be a germline alteration through germline testing. There were also biallelic inactivations of APC, TP53, and RB1. The patient received four cycles of induction chemotherapy with carboplatin and etoposide, achieving a partial radiographic response; however, treatment was complicated by cytopenias and significant fatigue. Immunotherapy was considered inappropriate as part of his initial systemic therapy regimen or as maintenance treatment due to the severe underlying autoimmune condition. Based on the germline BRCA2-mutated (gBRCA) status, we requested emergency approval for off-label use of talazoparib, a poly(ADP ribose) polymerase (PARP) inhibitor. At 12.5 months from initial diagnosis, including after 7.5 months on talazoparib, the patient continues to show ongoing radiographic response with excellent tolerability and no adverse effects. This case illustrates the potential role of PARP inhibitors in the management of BRCA2-mutated high-grade rectal NEC. Molecular profiling techniques may uncover actionable genetic targets in rare, aggressive cancers without standard treatment options or in patients with co-morbidities that preclude standard treatment regimens.

Keywords: PARP inhibitor; case report; gBRCA2 mutation; rectal neuroendocrine carcinoma; talazoparib.

Figure 1

CT and PET/CT imaging of the primary rectal tumor and regional lymph nodes before and after treatment. (A) Baseline axial contrast-enhanced CT scan (July 2024) demonstrates a large, semi-annular soft tissue mass in the low anterior left rectum (black arrow). (B) Staging Gallium-68 dotatate PET/CT (July 2024) reveals dotatate-avid mesorectal lymphadenopathy superior to the primary mass (white arrows). (C) Follow-up axial contrast-enhanced CT scan (March 2025), after systemic therapy, shows a significant treatment response with only minimal residual wall thickening at the tumor site (black arrow) and complete resolution of the lymphadenopathy.

Figure 2

MRI of the abdomen. (A) Baseline MRI of the abdomen. Axial T2-weighted fat suppressed MRI of the abdomen at baseline (August 2024) reveals innumerable, widespread T2-hyperintense hepatic metastases involving all segments of the liver (black asterisk denotes largest lesion). (B) Follow-up MRI of the abdomen. A follow-up axial T2-weighted fat suppressed MRI of the abdomen (August 2025), after approximately 7.5 months of talazoparib, demonstrates near resolution of the hepatic metastases, with only minimal residual signal abnormality within some of the initially largest lesions (white arrow).

Figure 3

Histopathology and immunohistochemical staining of the rectal neuroendocrine carcinoma. (A) Microscopic image of the biopsied colonic mucosa (left) showing a proliferation of atypical cells arranged in a solid architectural pattern (right). The cells exhibit high nuclear-to-cytoplasmic (N: C) ratios, scant cytoplasm, hyperchromatic nuclei, and prominent nuclear molding. (B) Higher-power magnification of the area of interest, demonstrating sheets of small ovoid cells with scant cytoplasm. Limited immunohistochemical analysis shows tumor cell positivity for CK Oscar, synaptophysin, and chromogranin, supporting epithelial neuroendocrine neoplasm. The Ki-67 proliferation index is markedly elevated, approaching 100%. The histomorphology and immunohistochemical profile are consistent with a diagnosis of high-grade, poorly differentiated neuroendocrine carcinoma. .