AACR 2024 | PETRA: saruparib in solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations

The PETRA trial is a first in human Phase I/IIa clinical trial of the first in class PARP1 selective inhibitor called saruparib, previously known as AZD5305. In this study, we assessed escalating doses of saruparib from the starting dose of 10mg all the way up to 140mg once a day. The background to therapy is that we currently have multiple first generation PARP inhibitors that are approved in different indications, and also different cancer types. However, these first generation PARP inhibitors are all PARP1 and PARP2 inhibitors. But research has told us and shown us that you really only need to block PARP1 for efficacy and the homologous recombination deficient setting. So with that in mind, saruparib was developed as a first in class, highly potent and highly selective PARP1 selective inhibitor. And during this trial, we tested the hypothesis in terms of safety, pharmacokinetics, pharmacodynamics, and also preliminary efficacy in patients who had selected homologous recombination deficient molecular subtypes as well as tumor types. So on this clinical trial, we mandated that all patients required either BRCA1 mutation or BRCA2, or a PALB2 or RAD51C or D mutation. Tumor types included and were limited to patients with breast, ovarian, prostate, and also pancreatic cancers. And with that, in mind, we recruited a total of over 300 patients in both dose escalation and in our dose optimization expansion cohorts. During those escalation, we found that saruparib was very safe and well tolerated, with a highly favorable safety profile, with very infrequent dose reductions and drug discontinuations. Importantly, we also found that we were able to achieve much higher fold coverage over the target effective concentration of saruparib versus all of the approved first generation PARP inhibitors. In addition to that, we saw really impressive pharmacodynamic effects, both in peripheral blood mononuclear cells and also in pad tumor biopsies taken, we saw greater than 90% population inhibition as a pharmacodynamic readout of activity. And most importantly for me, we have seen anti-tumor activity in patients across every single dose treated. And during our dose optimization, we compared three of these selected doses the maximum tolerated dose of 90mg once a day versus two lower doses 20mg and 60mg once a day, as per the Project Optimus initiative from the FDA. And what we found was that 60mg once a day was superior to both 20mg and to the 90mg once daily dosing of saruparib. And based on that, and following discussions with the FDA, 60mg once a day of saruparib was established as the recommended Phase II dose. Saruparib is currently in Phase III  clinical trial testing in prostate cancer.