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Background: We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer., Patients and Methods: Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life., Results: 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms., Conclusions: This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used., Clinical Trial Registration: Clinicaltrials.govNCT01610869., Competing Interests: Declaration of Competing Interest Professor Marcia Hall reports grants and personal fees from Clovis Oncology, BMS and Merck and personal fees from Roche, GSK/Tesaro, Astra Zeneca, Boehringer Ingelheim and Amgen outside the submitted work. Dr. Susana Banerjee reports personal fees from Roche, AstraZeneca, GSK/Tesaro, Clovis Oncology, Pharmamar, Seattle Genetics, Merck Serono, Amgen and Genmab; grants from Astra Zeneca and GSK/Tesaro and travel support from Nucana all outside the submitted work. Dr. Rosemary Lord reports personal fees from Tesaro and Astra Zeneca, outside the submitted work. Dr. Andrew Clamp has received research funding and personal fees from Astra Zeneca, and personal fees from Clovis Oncology, Astra Zeneca, GSK/Tesaro, and Roche outside the submitted work. Dr. Shibani Nicum reports grants and personal fees from Astra Zeneca and personal fees from MSD, Roche, Abbvie, Clovis Oncology outside the submitted work. Professor J Ledermann has received fees for Advisory Boards, lectures, symposia from Boehringer Ingelheim, Astra Zeneca, MSD/Merck, Amgen, Artios, GSK/Tesaro, Eisai. He has received research funding from MSD/Merck and AstraZeneca, all outside the submitted work. Dr. Rebecca Bowen reports personal fees from Roche, AstraZeneca, GSK/Tesaro, Clovis Oncology, Amgen, Celgene and Lily Oncology, outside the submitted work. Dr. Agniescka Michael reports personal fees from Roche, outside the submitted work. Dr. Ros Glasspool reports research funding from Boehringer Ingelheim for the NiCCC clinical trial, further research funding from Lilly/Ignyta and personal fees from AstraZeneca, MSD, Clovis, GSK/Tesaro, Immunogen and Sotio outside the submitted work. Professor Gordon Rustin reports personal fees from Abbvie, outside the submitted work., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial., Methods: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017)., Results: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured., Conclusion: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer., Trial Registration: ClinicalTrials.gov identifier: NCT01847274., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare tumor typically affecting young women. It is an aggressive malignancy with a poor prognosis and few long-term survivors., Objective: Investigate the outcome of patients with SCCOHT., Method: Data were collected for patients with SCCOHT treated in Australia, Canada and Europe. Information included stage, surgery, chemotherapy, radiotherapy, recurrence and survival., Results: The median follow-up is 13 months for all patients and 35.5 months in surviving patients. Ten patients had FIGO stage I tumors, six stage III tumors and one stage unknown. All underwent surgical resection. Adjuvant platinum-based chemotherapy was given to all patients. Seven received adjuvant radiotherapy with either pelvic and para-aortic radiotherapy, average dose 46.5 Gy (40 Gy/25# - 50.4 Gy/23#), or pelvic and whole abdominal radiotherapy, average dose 45 Gy to pelvis and 25 Gy (22.5 Gy/22# - 30 Gy/25#) to abdomen. The median survival for stage I tumors was not reached and was 6 months for stage III tumors. For the ten patients with stage I tumors: six received adjuvant radiotherapy with five alive and disease-free; four received no adjuvant radiotherapy with one alive and disease-free, while three have relapsed with one alive and disease-free after resection. Of the seven patients with stage III or unknown stage tumors, all but one have died. Recurrences were most frequent in the pelvis and the abdomen. Patients receiving salvage treatment with chemotherapy and radiotherapy did poorly., Conclusion: We advocate a multi-modality treatment approach including surgery, chemotherapy with the addition of radiotherapy either sequentially or concurrently.

There is a subgroup of patients with Stage II or III ovarian cancer whose survival is poor despite optimal cytoreduction of tumor and abdominopelvic radiation. This study examined whether the survival of these patients, who have tumor with unfavorable histopathological characteristics and/or small residual disease, could be improved by giving chemotherapy before radiation. Forty-four out of fifty-one eligible patients, seen between 1981 and 1985, with Stage II or III disease were entered into the study. Following six courses of cisplatin-based chemotherapy, 33 (75%) received abdominopelvic radiotherapy. Survival was compared to that of 48 eligible matched control patients, treated with radiation between 1978 and 1981. The median follow-up is 6.6 years. The median survival was extended from 2.4 to 5.7 years (P = 0.13), and 42.6% of patients receiving combined therapy were free of relapse at 5 years, compared to 21.6% (P = 0.03) in the historical control group, treated with abdominopelvic irradiation alone. Only 2 of 44 patients in the combined group required surgery for bowel obstruction, as did 1 of 48 in the control group. Tolerance and toxicity of the combined approach were acceptable. Although we cannot be certain that the entire benefit we observed was not attributable to the chemotherapy alone, there is evidence that the radiotherapy may have been additive. Chemotherapy followed by abdominopelvic radiotherapy seems a reasonable management policy in these patients.