Next-Generation AstraZeneca PARP1 Inhibitor Shows Activity in Multiple Cancers at Variety of Doses

April 12, 2022 1:12 pm

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AACR 2022 annual meeting logo

by Alison Kanski

NEW YORK – An investigational AstraZeneca drug that showed activity at a range of doses across differently mutated cancers with limited toxicity exemplifies the versatility of next-generation PARP1 inhibitors, according to researchers at the American Society for Cancer Research’s annual meeting.

Researchers presented results at the meeting from the Phase I/IIa PETRA study of AstraZeneca’s investigational PARP1 inhibitor AZD5305 in advanced breast, ovarian, prostate, or pancreatic cancer patients bearing germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations.

Enrolled patients had received a variety of prior therapies, including platinum-based chemotherapy or PARP inhibitors and included some who were PARP inhibitor naïve.

In this first-in-human data from 40 evaluable patients, treatment with AZD5305 led to responses in 10 patients (25 percent) and stable disease in 11 patients (27.5 percent) across tumor types and mutation-defined subgroups. The median treatment exposure was 2.1 months, and 19 patients remained on treatment for over 16 weeks.

Notably, responses were also seen across dose levels, which ranged from 10 mg to 140 mg, Timothy Yap, associate professor of investigational cancer therapeutics at MD Anderson Cancer Center and an investigator on this study, said in the presentation. When looking at previous treatments, responses were seen in patients with platinum-resistant ovarian cancer and in patients regardless of prior PARP inhibitor treatment.

The researchers further explored other potential predictors of response to AZD5305. One such biomarker may be an early decrease in circulating tumor DNA (ctDNA). Eight out of 13 patients with ctDNA analysis saw a decrease in ctDNA levels at the start of cycle 2 compared to baseline. Five of these patients, who had BRCA2-mutant prostate cancer and hadn’t received a PARP inhibitor previously, saw a greater than 50 percent decrease in ctDNA after AZD5305 treatment.

In the PETRA study, no patients discontinued treatment due to adverse events. Patricia LoRusso, associate director of innovative medicine at Yale Medicine, noted in a discussion of the study results that AZD5305 had a wide therapeutic window. “This drug lends itself, with its phenomenal dosing flexibility, to combination with other agents to circumvent toxicity,” she said.

“Even with exposure above the target effective dose, there was very little toxicity,” she went on. “This drug offers several dosing advantages in the neoadjuvant or adjuvant setting, but potentially as monotherapy in the adjuvant setting.”

To LoRusso, the efficacy of AZD5305 at low doses suggests that it may be a candidate for preventive treatment of women with germline BRCA1/2 mutations, or other homologous recombination deficiency mutations, who don’t want to undergo preventive surgery. At a different session at this meeting on Friday, Susan Domchek, executive director of the Basser Center for BRCA at the University of Pennsylvania, discussed the potential of AstraZeneca’s lead PARP inhibitor Lynparza (olaparib) to be used for cancer prevention.

The low toxicity of AZD5305, a PARP1 inhibitor, also lends itself to combination strategies, which can be more difficult for currently marketed PARP inhibitors like Lynparza, Clovis Oncology’s Rubraca (rucaparib), and GlaxoSmithKline’s Zejula (niraparib). These earlier generation PARP inhibitors tend to be more toxic due to their inhibition of both PARP1 and PARP2, LoRusso said.

Yap compared the safety data from the PETRA study with previous trials of first-generation PARP inhibitors, noting that only 3 percent of AZD5305-treated patients required a dose reduction, compared to between 25 percent and 53 percent of patients on first-generation PARP inhibitors needing a reduction.

“The emerging safety profile of AZD5305 is highly favorable compared to first-generation PARP inhibitors across all key graphics,” Yap explained. “For example, rates of nausea and vomiting were numerically lower, and hematological toxicities were comparable or improved despite this being a heavily pretreated Phase I population.”

Given the treatment’s favorable toxicity profile, researchers have begun combination studies with AZD5305. In the dose expansion phase of the PETRA study, researchers have started enrolling patients in combination arms to explore the PARP inhibitor’s activity with chemotherapy, Daiichi Sankyo and AstraZeneca’s Enhertu (trastuzumab deruxtecan), and their investigational anti-HER2 antibody datopotamab deruxtecan.

Yap noted that in the development of AZD5305, researchers hoped it would deliver greater efficacy and tolerability than first-generation PARP inhibitors.

“The hypotheses behind the development of AZD5305 was that it would offer an improved tolerability profile versus first-generation PARP inhibitors; deliver higher and more durable drug exposure on target; achieve greater and more durable target inhibition; improve on the efficacy delivered by first generation PARP inhibitors; and enable broader combination options,” Yap said.

This article was published by Precision Oncology News.

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