Next-generation PARP inhibitor shows clinical benefit in certain patients with breast cancer
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Key takeaways:
- Saruparib at 60 mg/day demonstrated deep, durable responses with a high response rate and tumor reduction in most patients.
- Certain patients may be able remain on treatment longer at an optimal dose.
Saruparib conferred clinically impactful treatment outcomes among adults with breast cancer who harbor certain genetic mutations, according to data presented at American Association for Cancer Research Annual Meeting.
Researchers also reported a favorable safety profile for the investigational agent, along with a low dose reduction rate compared with certain approved [poly(ADP)-ribose polymerase (PARP)] inhibitors.
“The excellent safety and tolerability profile, along with the favorable pharmacokinetic and pharmacodynamic properties, may enable patients to remain on saruparib treatment with sustained maximal target engagement and limited dose reductions or discontinuation,” Timothy A. Yap, MBBS, PhD, professor of investigational cancer therapeutics and vice president and head of clinical development at The University of Texas MD Anderson Cancer Center, said in a press release.
Background, methods
Saruparib (AstraZeneca) is a first-in-class polymerase-1 selective inhibitor with PARP1 selectivity and potency shown through preclinical trials.
The phase 1/phase PETRA trial is evaluating the safety, tolerability and efficacy of saruparib among 306 adults with homologous recombination repair-deficient breast, ovarian, pancreatic or prostate cancer who harbor certain genetic alterations. Safety and tolerability served as the study’s primary endpoints, with secondary endpoints evaluating pharmacokinetics, pharmacodynamics, preliminary efficacy and circulating tumor DNA (ctDNA) analysis.
Dose escalation comprised part A, ranging from 10 to 140 mg daily, whereas part B included dose expansions at 20/40/90 mg daily among PARP inhibitor-naive patients.
Results, next steps
Researchers observed the 60 mg/day dose as well tolerated by patients, with low rates of dose reduction or treatment discontinuation.
Saruparib displayed higher-fold pharmacokinetic coverage over the target effective concentration for all doses compared with approved PARP inhibitors and durable poly ADP-ribosylation inhibition.
Upon interim analysis, researchers observed that the objective response rate in patients with breast cancer trended higher at 60 or 90 mg vs. 20 mg, with 60 mg/day being the recommended phase 2 dose.
Among patients who received the 60 mg/day (n = 31), researchers noted an objective response rate of 48.4% (80% CI, 35.7-61.3) and a median PFS of 9.1 months (80% CI, 7.2-9.3).
Patients in which ctDNA could be evaluated exhibited a molecular response prior to their first scan, which researchers indicate predicted PFS, thus supporting ctDNA kinetics as an early predictive biomarker for efficacy.
According to researchers, all currently approved PARP inhibitors block both PARP1 and PARP2, which limits utility due to toxicity. They believe this interim analysis of the PETRA trial demonstrates the clinical effectiveness and safety of saruparib among patients with homologous recombination repair-deficient breast cancers.
“The favorable safety profile of saruparib together with the low dose reduction rate compared with approved PARP inhibitors may allow patients to remain on treatment longer at an optimal dose with superior drug exposures and maximal target engagement, which could lead to improved efficacy,” Yap said during a presentation. “Further evaluation of saruparib in the phase 3 trial setting is ongoing at the recommended phase 2 dose of 60 mg daily.”
References:
- Next-generation PARP inhibitor demonstrated clinical benefit in patients with homologous recombination repair-deficient breast cancer (press release). Available at:https://www.aacr.org/about-the-aacr/newsroom/news-releases/next-generation-parp-inhibitor-demonstrates-clinical-benefit-in-patients-with-homologous-recombination-repair-deficient-breast-cancer. Published April 8, 2024. Accessed April 8, 2024.
- Yap TA, et al. Abstract CT014. Presented at: The American Association for Cancer Research Annual Meeting; April 5-10, 2024; San Diego.
Perspective
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Nancy Chan, MD
There are other PARP inhibitors that have come before Saruparib, but what makes Saruparib unique is that it is highly selective for PARP-1, which is the enzyme that “calls” other cells when there is damage at the DNA level. This entire class of drugs works by preventing PARP-mediated DNA damage repair of single-stranded DNA breaks.Historically, the side effects of these drugs are mostly hematologic. For example, they may be associated with low blood counts that either require discontinuing the medication or dose adjustment.
It seems that this drug has fewer of these side effects, which may potentially increase the duration that a patient is able to stay on this drug. For a drug to be effective, we have to make sure patients are able to tolerate it. This is one of the potential benefits of having a more specifically targeted PARP inhibitor that can offer a long and durable response.
Because this was a first-in-human study, the primary endpoint was still safety and tolerability, but we had several very interesting, exploratory endpoints as well. For example, the researchers looked at CT DNA analysis, which looks not only at attaining an image response, but also a molecular-level response. I think that will be very important.
Preliminarily, I think there is a correlation between being able to lower the amount of CT DNA presence and improvement in progression-free survival. This remains to be confirmed, but this is an interesting direction as we increasingly look into CT DNA tracking, especially serially in metastatic cancer patients.
The bottom line is that this is a potential new option that blocks more specifically at the target and may enable patients to remain on this medication longer. This is very important because this is not chemotherapy, so if it is effective, it could truly improve quality of life in patients who are able to tolerate it.
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Yap TA, et al. Abstract CT014. Presented at: American Association for Cancer Research Annual Meeting; April 5-10, 2024; San Diego.
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