First-in-Class PARP1 Selective Inhibitor Saruparib Shines in Phase 1 Trial of Advanced Solid Tumors

The first-in-class PARP1 selective inhibitor saruparib (AZD5305) elicited promising response rates across all dose levels and was well tolerated in patients with advanced solid tumors that harbored BRCA1/2, PALB2, and RAD51C/D mutations, according to Timothy Yap, MBBS, PhD, FRCP.

“We have now developed a first-in-class PARP1 selective inhibitor which is differentiated from the first generation PARP1 and PARP2 inhibitors that are already approved. We believe that we can get much greater bang for [our] buck with this new class of PARP1 selective drugs,” Yap said. “[With saruparib] we’ve seen a very promising safety profile, pharmacokinetic and pharmacodynamic profile, and importantly efficacy.”

Data from the phase 1/2a PETRA trial (NCT04644068) presented by Yap at the 2024 AACR Annual Meeting revealed that patients who received saruparib 60 mg daily (n = 31) achieved an objective response rate (ORR) of 48.4% (80% CI, 35.7%-61.3%) with a median duration of response (DOR) of 7.3 months (80% CI, 5.6-7.6). The median time to response from first dose was 3.5 months (80% CI, 1.9-3.6) and the median progression-free survival (PFS) was 9.1 months (80% CI, 5.7-9.3).

Furthermore, in the 20 mg daily cohort patients (n = 28) experienced an ORR of 35.7% (80% CI, 23.5%-49.6%) with a median DOR of 6.1 months (80% CI, 3.8-7.4) and in the 90 mg daily cohort patients (n = 30) experienced a median ORR of 46.7% (80% CI, 33.8%-59.9%) with a median DOR of 5.6 months (80% CI, 5.6-7.4).

In an interview with OncLive®, Yap detailed additional findings from the study and explained next steps with the first-in-class PARP1 selective inhibitor. Yap is a professor in the Department for Investigational Cancer Therapeutics (Phase I Program) and the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. He is also vice president and head of Clinical Development in the Therapeutics Discovery Division and associate director of Translational Research in the Khalifa Institute for Personalized Cancer Therapy.

OncLive: What was the rationale for investigating saruparib in patients with advanced solid tumors and genetic mutations?

Yap: We currently have 4 approved PARP inhibitors in the clinic which are effective and have shown benefit in patients. However, they are associated with adverse effects [AEs] including fatigue; myelosuppression such as anemia, thrombocytopenia, and neutropenia; and gastrointestinal AEs such as nausea, vomiting, and diarrhea. We need to build on that success and develop drugs that will show great efficacy with minimal AEs.

To shrink cancers and benefit patients, we only need to potently block or inhibit PARP1; all the approved PARP inhibitors are potent PARP1 and PARP2 inhibitors and trappers. The hypothesis [for this trial] is that by dialing out PARP2 and focusing on developing a highly potent and selective PARP1 inhibitor one can achieve that. [Thus], the first-in-class PARP1 selective inhibitor saruparib was developed which we then brought into the clinic with the PETRA trial.

PETRA is a first-in-human phase 1 and 2a clinical trial comprised of a dose-escalation phase followed by a dose-optimization expansion phase. During dose escalation, we enrolled patients who had breast, ovarian, prostate, and pancreatic cancers; we mandated that they had to have either BRCA1, BRCA2, PALB2, RAD51C,or RAD51D mutations. There was no limit on [the number of] prior chemotherapies or prior lines of treatment [that were allowed], so it was a heavily pretreated patient population. The hemoglobin requirements for this trial were more flexible and during dose escalation we explored doses ranging from 10 mg to 140 mg given once a day.

What key data were seen with saruparib in PETRA?

Saruparib was well tolerated with fewer AEs [compared with approved PARP inhibitors]—mainly grade 1 to grade 2 [AEs occurred with saruparib]. There were fewer dose interruptions, dose reductions, and drug discontinuations with saruparib vs the first generation PARP1 and PARP2 inhibitors.

Importantly, much higher drug exposures [were achieved with saruparib compared with] the first generation PARP1 and PARP2 inhibitors, indicating that by dialing out the PARP2 inhibition we could push the dose of PARP1 inhibition in patients. Very robust pharmacodynamic effects [were also achieved] in terms of hitting the target and blocking PARP1; PARylation inhibition was achieved by greater than 90% in both peripheral blood mononuclear cells measured in all patients and in paired tumor biopsies.

Responses were seen during dose escalation at every dose level, and that provided the rationale to proceed to the dose-optimization expansion cohort as per Project Optimus from the FDA. In the expansion cohort, we compared 3 different dose levels of 20, 60, and 90 mg, where 90 mg was the maximum-tolerated dose. [Saruparib] was well tolerated with a very favorable AE profile [and] infrequent dose interruptions, reductions or discontinuations [occurred]. Much higher and greater drug exposures [as well as] pharmacodynamic effects [were achieved].

Most importantly, at the recommended phase 2 dose of 60 mg once daily, we saw an ORR of 48.4% and a median PFS of 9.1 months.

What are the next steps for investigating saruparib?

This drug should be explored and studied in different cancer types and different mutations as well. Currently, saruparib is [being evaluated] in the phase 3 [EvoPAR-PR01] clinical trial [NCT06120491] for patients with prostate cancer and that’s going to be in combination with new hormonal agents. Other studies are also planned.

During the PETRA trial, the most common alterations were the BRCA1 and BRCA2 mutations as expected, followed by the PALB2 and RAD51C/D mutations. It’s hard to tease out the difference [in efficacy] between [the mutations thus far]; that’s something that we will look more deeply into in further studies.

Reference

Yap TA, Schram AM, Balmaña J, et al. PETRA: first-in-human phase 1/2a trial of the first-in-class next-generation poly(ADP-ribose) polymerase-1 selective inhibitor (PARP1i) saruparib (AZD5305) in patients (pts) with advanced solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT014.