The findings of a study led by the University of Leicester suggest rucaparib can improve disease control in BAP1-deficient or BRCA1-deficient malignant mesothelioma.
The researchers carried out a single-centre, open-label, single-arm, phase 2a trial with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]).
Patients aged 18 years or older who had radiologically progressing, histologically confirmed cytoplasmic-BAP1-deficient or BRCA1-deficient malignant mesothelioma after at least one course of systemic treatment were included.
All participants received oral rucaparib 600 mg twice daily for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent or death.
Response was measured by computed tomography scan every six weeks. The primary outcome was disease control (complete response, partial response or stable disease) at 12 weeks. Secondary outcomes were safety and toxicity, objective response rate (proportion of complete or partial responses) and disease control rate at 24 weeks.
Between 9 February 2019 and 10 June 2019, 26 were eligible for inclusion. Ten (38%) of the 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative and 13 patients (50%) were BRCA1 negative.
Disease control rate at 12 weeks was 58 per cent (95% CI, 37%-77%), and at 24 weeks was 23 per cent (95% CI, 9%-44%).
Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients. There were no deaths. The most common grade 1-2 adverse events were nausea (69%), fatigue (54%) and decreased appetite (38%). The most common grade 3-4 adverse events were upper respiratory tract infection (12%) and anaemia (12%).
All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%).
Rucaparib met the prespecified criteria for success, showing promising activity with manageable toxicity.
Further investigation of homologous recombination deficiency mutations is now planned to refine the identification of predictive biomarkers for poly (ADP-ribose) polymerase inhibition in mesothelioma.
