196P - Randomized phase II study of trabectedin/olaparib compared to physician’s choice in subjects with previously treated advanced or recurrent solid tumors harboring DNA repair deficiencies

Background

Genomic aberrations affecting the repair of DNA double-strand breaks (DSB) by homologous recombination (HR) are found in various cancers and result in sensitivity to inhibitors of the DNA repair enzyme PARP1. Trabectedin induces DNA DSB and PARP1 activation and may thus increase the effect of PARP inhibitors in HR-deficient cancers. Whole-exome/genome sequencing (WES/WGS) can identify mutations in DNA repair pathways and mutational signatures generated by these aberrations.

Methods

We present the preliminary results of the final data from a randomized phase II trial comparing trabectedin and olaparib (TrO) with treatment of physician’s choice (PC) in adults with advanced/metastatic cancers with defective HR DNA repair (“BRCAness”), as determined by WES/WGS. Molecular eligibility was determined based on a newly developed BRCAness score. Main exclusion criteria were hematologic/primary brain cancers, ECOG PS >1, prior PARP inhibitor treatment. Patients were randomized 1:1 to TrO (days 1/1-21) vs. PC, and treated until disease progression (PD). Cross-over upon PD was allowed. The primary endpoint was disease control rate (DCR; CR, PR and SD [RECIST 1.1]) at 16 weeks. Platinum-refractory disease was added as exclusion criterion at first amendment.

Results

From November 2018 till June 2023, 117 patients have been randomized (TrO, n=60; PC, n=57). Various entities were included (sarcoma, n=52; cholangiocarcinoma, n=7; pancreatic cancer, n=6; gynecologic cancer, n=13; uveal melanoma, n=5; other, n=35); prior treatment was balanced between arms. Main AEs associated with TrO were cytopenias, infections and gastrointestinal side effects. A median of 3 treatment cycles were applied; PD was the main cause of treatment termination. Cross-over to TrO occurred in 62%. Patients with patinum-refractory disease (n=16) were excluded. DCR was 33.3% in TrO and 38.5% in PC (p=0.68), while the DCR after cross-over was 38,5% at week 16; PRs were observed in n=8 patients. Median PFS and overall survival (OS) was 2,9 months (95%-CI, 2.1-4.8 months) and 19.4 months (95-CI, 13.5-24.1 months).

Conclusions

TrO was not superior to PC in the entire study population.

Clinical trial identification

EudraCT 2017-001755-31; NCT03127215; AIO Trial No. AIO-STS/TF-0117/ass.

Editorial acknowledgement

Legal entity responsible for the study

Heidelberg University Hospital.

Funding

German Ministry of Education and Health, PharmaMar, AstraZeneca.

Disclosure

R.F. Schlenk: Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pfizer, PharmaMar, Roche, Recordati; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, Pfizer, AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer, Jazz, Daiichi Sankyo, AbbVie. S. Richter: Financial Interests, Personal, Advisory Board: PharmaMar, Bayer, Deciphera, PharmaMar, Bayer, Deciphera, Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria: PharmaMar, Boehringer Ingelheim, Deciphera; Financial Interests, Institutional, Research Funding: PharmaMar, Boehringer Ingelheim, Deciphera; Financial Interests, Personal, Other, Travel Grants: PharmaMar, Boehringer Ingelheim, Deciphera. J.T. Siveke: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Servier, Immunocore, PSL Group, Novartis, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Roche, MSD Sharp & Dohme, MCI Deutschland, Falk Foundation; Financial Interests, Personal, Stocks/Shares: FAPi Holding AG; Financial Interests, Institutional, Coordinating PI, Trial support: AstraZeneca, Bristol Myers Squibb, Roche/Genentech; Financial Interests, Institutional, Research Grant, Project support: Abalos Therapeutics, Boehringer Ingelheim, Eisbach Bio GmbH. H. Kopp: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Roche, Pfizer, Takeda, Sanofi/Aventis, Lilly; Financial Interests, Personal, Advisory Board: MSD, Novartis, MSD, BMS, AstraZeneca; Financial Interests, Personal, Writing Engagement: Boehringer Ingelheim. L. Illert: Financial Interests, Personal, Advisory Board: AbbVie, Janssen-Cilag; Financial Interests, Personal, Other, Honoraria: Roche, AstraZeneca, Ars Tempi, Takeda; Financial Interests, Personal, Other, Travel Grants: Roche, AstraZeneca, Janssen-Cilag, Takeda. K. Dorman: Financial Interests, Personal, Other, Travel Grants: Servier, GSK, Bristol Myers Squibb, AstraZeneca; Financial Interests, Personal, Other, Honoraria: AstraZeneca. C. von Kalle: Financial Interests, Personal, Advisory Board: Ad hoc advisor to or paid speaker for multiple (>20) pharmaceutical and medtech companies, not related to this work.. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. C.E. Heilig: Financial Interests, Institutional, Funding, Research Funding: AstraZeneca, Pfizer, Roche, PharmaMar. All other authors have declared no conflicts of interest.