Abstract LB-273: A head-to-head comparison of the properties of five clinical PARP inhibitors identifies new insights that can explain both the observed clinical efficacy and safety profiles

Abstract

Four poly(ADP-ribose) polymerase (PARP) inhibitors have now presented phase 3 monotherapy data showing compelling benefit of targeting tumours enriched with DNA damage response (DDR) pathway deficiencies, including BRCA gene mutations. Indirect treatment comparisons using the published clinical data from these late stage trials suggest similar levels of monotherapy efficacy are observed in spite of reported differences in PARP trapping potency. However, there is greater diversity in the observed safety profiles. To try and understand these observations, we have carried out a head-to-head comparison of these four PARP inhibitors (olaparib, niraparib, rucaparib and talazoparib) as well as veliparib, which recently reported phase 3 chemotherapy combination data. In our studies, we included an assessment of molecular mechanism of action that included PAR inhibition, PARP trapping and synthetic lethality in isogenic BRCA mutant and wild type models. In addition, an assessment of selectivity in terms of both inhibition of PARP family members using a novel chemoproteomic approach, as well as secondary (off-target) activities was performed. Finally, effects on human haematopoietic stem cell viability and bio-distribution to bone marrow in the rat were tested and compared. A detailed correlation of our datasets with the observed clinical results, including adverse events, suggests these preclinical experiments provide an excellent predictor of clinical response and could be used to assess emerging as well as novel PARP inhibitors. OlaparibVeliparibRucaparibNiraparibTalazoparibCompanyAZAbbVieClovisTesaroPfizerPhaseApprovedIIIApprovedApprovedIIIPARP1 SPR Kd (µM)0.0010.0070.0010.0130.002PARP2 SPR Kd (µM)0.0010.0140.0230.0430.005PARPs with Proteomic Kd <1 µM1,2,3,4,131,2,3,4,131,2,3,4,10,131,2,131,2,3,4,5a,13, 16Sec. Pharm. #, top hit µM0/855/85 5HT7, 0.513/85 5HT4, 0.517/84 DAT, 0.040/85Monotherapy dose (mg)300 bd (tablet)500 bd600 bd300 od1 od Citation Format: Elisabetta Leo, Jeffrey Johannes, Giuditta Illuzzi, Andrew Zhang, Paul Hemsley, Michal J. Bista, Jonathan P. Orme, Verity A. Talbot, Ana J. Narvaez, Elizabeth Underwood, Andrew Pike, Jenni K. Nikkila, Lucy Riches, Sinbad Sweeney, Frida Gustafsson, Anna Cronin, Piero Ricchiuto, Debora A. Roaquin, Fiona Pachl, Eric Miele, Ruth MacDonald, Glen Hawthorne, Andrew N. Mead, Mark J. O'Connor. A head-to-head comparison of the properties of five clinical PARP inhibitors identifies new insights that can explain both the observed clinical efficacy and safety profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-273.

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

“…For example, a recent study by Leo and colleagues comparing all aforementioned PARP inhibitors, apart from pamiparib, showed that the cytotoxic potential of each of the five PARP inhibitors differs between HRR-deficient (HRD) and HRR-proficient isogenic cell lines, whereby olaparib showed the most HRD-specific sensitivity, and talazoparib was the most agnostic to HRR status with regard to its cytotoxicity. Veliparib displayed the least efficacy in both the HRD and HRR-proficient lines (24).…”

“…1; refs. 23,24). In addition, sequential tumor and/or liquid biopsies in PARP inhibitor-treated preclinical models and patients are giving researchers a better understanding of the underlying mechanisms of sensitivity and resistance to this class of drugs, potentially paving the way forward for the development of functional biomarkers for rational patient selection.…”

“…1; refs. 24,25). Clinical studies of PARP inhibitors have used the quantification of PAR chain formation in peripheral blood lymphocytes as a pharmacodynamic biomarker, demonstrating that they can cause the acute and complete inhibition of PARP enzymatic activity, even at subtherapeutic doses.…”

“…Rather, as described above, PARP trapping, in addition to the inhibition of catalytic activity, also requires a slow "off-rate," and as long as the inhibitor is bound to the active site, NAD cannot be utilized for auto-PARylation and DNA dissociation. Talazoparib is able to bind chromatin and create these trapped PARP-DNA complexes to an approximately 100-fold greater degree than rucaparib, niraparib, or olaparib, whereas veliparib displays negligible PARP-trapping ability (23)(24)(25)(26). Although preclinical data on pamiparib is more limited than the other PARP inhibitors, a study in cell line models showed that this drug is able to form PARP-DNA complexes at an IC 50 of 13 nmol/L.…”

“…Although the underlying mechanisms for this clinical phenomenon are still unclear, they have important implications for encouraging patients and physicians to continue PARP inhibitor therapy at their starting doses while optimizing supportive therapies. The frequency and grade of cytopenias do seem to differ between PARP inhibitors in clinical trials carried out to date, with talazoparib arguably showing the highest occurrence of cytopenias, particularly anemia and neutropenia (20), followed by niraparib (24,29), with high rates of grade 3 or greater thrombocytopenia and neutropenia in particular, and then olaparib (21,30,31) and rucaparib (32) with similar lower rates of all cytopenias versus talazoparib and niraparib. Although a direct comparison between these trials is not possible given that they are in distinct patient populations, it is notable that the rate of occurrence of grade 3 or higher bone marrow suppression tends to mirror the respective PARP-trapping ability of these PARP inhibitors.…”