AACR 2024 – Astra plays up PARP1 inhibition

While AstraZeneca has moved speedily to get its PARP1-selective inhibitor saruparib into a pivotal trial in first-line prostate cancer, it used AACR to play up this asset’s safety. However, this has been shown only on a cross-trial basis, with a focus not on prostate but on breast cancer.

The data, unveiled yesterday at the conference, concern the multi-cohort first-in-human Petra trial, which yielded early data from its dose-escalation phase two years ago. Now Astra is highlighting the results of a 60mg daily saruparib dose: true, this appears to show better efficacy than Lynparza, with somewhat lower toxicity, but the effect isn’t as striking as might have been expected.

In terms of efficacy the most impressive number with 60mg was 9.1 months of median PFS among 31 patients. This compares favourably against Lynparza’s Olympiad trial, which on mPFS scored 7.0 months. Of course these two studies recruited patients with different baseline characteristics, and Petra might represent more severe disease, but there was no difference between them on remission rates.

Presenting the Petra update MD Anderson’s Dr Timothy Yap pointed to safety as the differentiator, in particular citing a lower rate of dose reductions than with Lynparza and other standard PARP inhibitors. Nevertheless, rates of severe adverse events weren’t that different, and higher dosing showed saruparib to result in significant adverse events.

Maximum tolerated dose

In terms of guiding saruparib’s late-stage development Petra identified 60mg once daily as the dose to take forward. The phase 3 Evopar-Prostate01 study, in first-line hormone-sensitive prostate cancer, got under way last November, pitting the PARP1 inhibitor plus novel hormonal agent (Zytiga, Xtandi or the like) versus a novel hormonal agent alone.

That was chosen after Petra’s dose-escalation stage showed 90mg daily to be maximally tolerated, and dose expansion was carried out at 20mg, 60m and 90mg. It was these three doses that featured at AACR, specifically in 89 patients whose HER2-negative breast cancer harboured BRCA1/2, PALB2 or RAD51C/D mutations.

First results, presented at AACR two years ago, showed five partial responses among 46 patients with various cancers. While dose-escalation patients could have received a standard PARP inhibitor, those in dose expansion were PARP inhibitor naive, and this now allows a neat cross-trial comparison in breast cancer against Lynparza’s Olympiad study. 

Astra argues that blocking PARP1 alone might be enough to generate sufficient efficacy, but approved PARP inhibitors hit PARP2 also, a fact that brings with it toxicity and limits dosing. The big question is whether such an effect be discerned clinically.

In this respect Petra shows quite neatly that efficacy rises up to 60mg, with an acceptable level of side effects. Above 60mg toxicity jumps alarmingly with no added efficacy benefit. This is a positive finding, albeit from a small, uncontrolled trial, whose results may or may not be repeated in larger studies.

Cross-trial comparison in BRCAm, relapsed, HER2-negative breast cancer

Source: prescribing information & AACR.

It’s a separate question whether saruparib will show a similar safety/efficacy balance across indications other than breast cancer.

Petra’s early data cut in 2022 showed prostate cancer patients yielding PSA50 responses, and this likely guided the quick move into phase 3 in this indication. As for breast cancer, Yap told yesterday’s AACR press conference that a late-stage saruparib study in this setting would be launched in the coming days.

Given that PARP1-selective targeting might result in a wider therapeutic window it might be surprising how few companies have jumped into this space. Perhaps the problem lies in the difficulty of designing a true PARP1-selective inhibitor, but it’s also possible that the data have so far not been convincing enough to drive such efforts.

Gilead and Merck KGaA have both followed Astra into PARP1-selective inhibition, but apart from this trio OncologyPipeline reveals just three other companies with clinical-stage assets: Eikon (with EIK1003), Jiangsu Hansoh (HS-10502) and Synnovation (SNV1521).