Hurley, Rachel

Abstract Despite long-standing interest in combining topoisomerase I (TOP1) poisons with PARP inhibitors (PARPis), the mechanistic basis for the variable and often unpredictable response to this strategy remains unclear. Early preclinical studies suggested that PARP inhibition amplifies TOP1 poison-induced DNA damage, implying broad therapeutic potential; however, emerging translational and clinical data—particularly in ovarian cancer—indicate that synergy is context-dependent and governed by tumor-intrinsic features that have not been fully defined.Here we assessed determinants of response in five HR proficient ovarian cancer (OC) patient-derived xenografts (PDXs) previously treated with the SN-38 prodrug etirinotecan pegol (NKTR-102) in combination with the PARPi rucaparib (C. Nitschmann, Clin. Cancer Res. 22(2) Suppl. B50, 2016). Although all models were refractory to single-agent rucaparib, 50% exhibited enhancement of NKTR-102-induced tumor regression with the addition of rucaparib. Neither PARP1 abundance nor extent of rucaparib-mediated poly(ADP-ribose) suppression correlated with therapeutic benefit. Instead, sensitization was restricted to PDXs intrinsically responsive to NKTR-102 and was strongly associated with high levels of NKTR-102-induced TOP1-DNA covalent complexes. In further analysis, 2 of 3 resistant PDXs exhibited high levels of the ABC transporter ABCG2 despite lack of previous therapy, revealing a previously underappreciated mechanism of de novo resistance that limits effective TOP1 inhibitor activity independent of homologous recombination status. Notably, NKTR-102 response did not track with platinum/taxane sensitivity, highlighting the distinct molecular circuitry governing TOP1 poison susceptibility.Collectively, these findings demonstrate that rucaparib can potentiate NKTR-102-induced regression in tumors capable of forming abundant TOP1-DNA covalent complexes. This work identifies TOP1-DNA complex trapping and lack of ABCG2 expression as mechanistic predictors of benefit, providing an updated framework for selecting patients most likely to respond to TOP1 poison/PARPi combinations and challenging the long-standing assumption that PARP inhibition can universally resensitize tumors to TOP1 poisons. Citation Format: Annapoorna Venkatachalam, Caroline C. Nitschmann, Karen S. Flatten, Rachel Hurley, Xiaonan Hou, Cristina Correia, Paula A. Schenider, Krista Goergen, Matthew Maurer, Ethan P. Heinzen, Ann L. Oberg, S John Weroha, Paul Haluska, Scott H. Kaufmann, Elizabeth M. Swisher. TOP1-DNA protein complex as a predictive biomarker for NKTR-102/Rucaparib combination therapy in PARP-inhibitor resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB364.

Abstract Background: Chemotherapy-induced peripheral neuropathy is characterized by pain, numbness, and tingling in the hands and feet and by diminished quality of life. Multiple previous studies, mostly preclinical, suggest that poly (ADP-ribose) polymerase (PARP) inhibitors may help with these symptoms. Objective: To assess the relationship between PARP inhibition and prevention/palliation of peripheral neuropathy in a clinical setting. Design: Meta-analysis of placebo-controlled clinical trials with PARP inhibitors. Setting/Subjects: We conducted 9 literature searches that included PubMed and other sources to compile fully published placebo-controlled clinical trials that tested PARP inhibitors and that reported on peripheral neuropathy. Measurements: The relative risks for neuropathy of all grades based on PARP inhibition were calculated for each trial. Each trial was weighted by its respective sample size. A forest plot was constructed. Results: Five trials, inclusive of 843 patients, met this study's eligibility criteria. Four included a concomitant PARP inhibitor (either olaparib or veliparib) and paclitaxel, a neuropathy-causing chemotherapy agent; the remaining trial evaluated long-term monotherapy with olaparib. The pooled overall relative risk for the development of neuropathy with PARP inhibition was 1.06 (95% confidence interval: 1–1.4). Conclusions: PARP inhibition does not appear to reduce the risk of chemotherapy-induced peripheral neuropathy. Whether PARP inhibitors may palliate (rather than prevent) neuropathy remains an area in need of further investigation.