Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial

Introduction: In ES-SCLC patients with residual intrathoracic disease after first-line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial. Materials/methods: Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation. Results: The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO = 0 performance status (24% vs 45%), and a higher proportion had WHO = 2 (15% vs 5%; p <0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p = 0.02) and PFS (p = 0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p = 0.03) and/or bone metastases (p= 0.04) were present. Discussion: This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases. (C) 2017 The Author(s). Published by Elsevier Ireland Ltd

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer

PARTNER is a prospective, phase II–III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1, 2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin–paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin–paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

Acknowledgements: We thank the patients, and the families and friends who supported them, for participating in this trial; our ethics committee, our independent data and safety monitoring committee and the trial management group for their advisory roles; the PARTNER trial consortium members, past and present (Supplementary Information); and I. Cizaite for preparing and proofreading the manuscript. This trial was sponsored by Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and financed by a project grant from AstraZeneca, who also supplied olaparib. Cancer Research UK provided peer review and endorsement for the study and financed the sample collections for the translational studies, which will be reported separately. We also acknowledge the National Institute for Health and Care Research Cambridge Biomedical Research Centre and the Cancer Research UK Cambridge Centre for their financial support for staff and infrastructure costs. The funders had no role in data collection or analysis. Once the trial group had interpreted the data, the results were then shared with the AstraZeneca scientists. In addition, we thank the Cancer Molecular Diagnostics Laboratory and The Precision Breast Cancer Institute Team for their support for sample collection; Cambridge Tissue Bank (NIHR203312) for sample assessment and diagnostics; Cambridge Clinical Trials Centre – Cancer Theme for their core staff support; the clinical trials support staff at all participating sites; and Addenbrookes Charitable Trust for financing the post of the chief investigator (2015–2018). We acknowledge Cancer Research UK (CRUKE/14/048) and AstraZeneca (1994-A093777).PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576