Journal Article Clinical Trial, Phase II Multicenter Study Ppublish
PubMed: 42710416 DOI: 10.1016/j.cllc.2026.08.001
Rationale and Study Design of the GUIDANCE trial: A Multicenter Phase II Trial of Maintenance Durvalumab and Olaparib After Standard Fist Line Treatment (Carboplatin/Cisplatin, Etoposide, and Durvalumab) in HRD Positive Extensive Disease (ED) Small-cell Lung Cancer (SCLC) (AIO-TRK-0124/ass).
Clin Lung Cancer 27(8):38-43
Authors: Richard Riedel, Malte Verheyen, Sebastian Michels, Lea Ruge, Sofia Stilianakis, Carolin Jakob, Heather Scharpenseel, Matthias Scheffler, Lucia Nogova, Karsten Schulmann, Farastuk Bozorgmehr, Christian Grohe, Frank Griesinger, Vanessa Welter, Jana Fassunke, Janna Siemanowski-Hrach, Yuri Tolkach, Udo Siebolts, Sabine Merkelbach-Bruse, Reinhard Büttner, Jürgen Wolf, Felix John
Affiliations
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne (LCGC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
- Division of Thoracic Oncology and Palliative Care, Department of Pneumology, Lungenklinik Hemer, Hemer, Germany.
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
- Department of Respiratory Diseases, Evangelische Lungenklinik, Berlin, Germany.
- Department of Haematology and Oncology, Pius-Hospital Oldenburg Medical Campus, Oldenburg, Germany.
- Faculty of Medicine and University Hospital of Cologne, Institute for Pathology, University of Cologne, Cologne, Germany.
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Lung Cancer Group Cologne (LCGC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Abstract
BACKGROUND
Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade.
METHODS
GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry.
DISCUSSION
This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.
MeSH
Cells, Genes, Recombination, Genetic, Lung, Poly(Adp-Ribose) Polymerases, Homologous Recombination, Neoplasms, Poly Adenosine Diphosphate Ribose, Biomarkers, Maintenance, Lung Neoplasms, Recombinational Dna Repair, Small Cell Lung Carcinoma, Therapeutics, Etoposide, Carboplatin