SAN DIEGO – Breast cancer patients whose tumors were HER2-negative but harbored certain deficiencies in homologous recombination repair (HRR) genes had encouraging responses to AstraZeneca's investigational PARP1 inhibitor saruparib and experienced fewer toxicities than what has been seen with marketed PARP inhibitors, researchers reported at the American Association for Cancer Research's annual meeting.
Timothy Yap, an oncologist who leads clinical development within MD Anderson Cancer Center's therapeutics discovery division, presented findings from the Phase I/IIa PETRA trial on Monday.
Although PARP inhibitor drugs are already routinely available for patients with various HRR-mutant tumors, Yap noted that the benefit of these drugs can be limited by their toxicities at high doses. Those drugs, however, target both PARP1 and PARP2. The advantage of a PARP1-specific inhibitor like saruparib may be that it causes fewer toxicities, which may, in turn, allow higher dosing.
Yap and colleagues designed the PETRA trial with two parts. In the dose escalation Part A, patients were eligible if they had a range of HRR-mutated advanced cancer types, including ovarian, pancreatic, prostate, and HER2-negative breast cancer. To participate in that first portion, patients could have received prior treatment with a PARP inhibitor. In the Part B dose expansion portion of the trial, patients were eligible if they had HER2-negative advanced breast cancers harboring mutations in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D, and if they hadn't received PARP inhibitors before.
Out of the 141 patients who received saruparib in this trial, Yap shared that 16 percent had to have their doses reduced due to a treatment-related side effect and 5 percent discontinued treatment due to toxicity. With the caveat that cross-trial comparisons have their limitations, Yap compared these data to prior clinical trials of commercially available PARP inhibitors, including Merck and AstraZeneca's Lynparza (olaparib), GlaxoSmithKline's Zejula (niraparib), Pfizer's Talzenna (talazoparib), and Pharma&'s Rubraca (rucaparib). In those trials, adverse event-related dose reductions were necessary for 25 percent to 53 percent of patients and 5 percent to 14 percent of patients discontinued treatment because of toxicities.
"Saruparib has a favorable safety profile and much higher pharmacologic target coverage than the approved PARP inhibitors," Yap said, noting that the safety profile was favorable even in the very heavily pretreated patient population. Indeed, in the dose-escalation portion of the PETRA trial, patients had received a median of three prior therapies and 45 percent of them had received prior PARP inhibitors.
Yap said that in the second part of the trial, which was limited to breast cancer patients who had not received PARP inhibitors previously, 31 patients received a 60 mg daily dose of saruparib, which Yap, in collaboration with the US Food and Drug Administration through its Project Optimus framework, determined to be the best dose for Phase II trials. In these patients, the objective response rate was 48.4 percent on saruparib. Patients lived a median 9.1 months without their cancers progressing, although Yap noted that the progression-free survival data for patients on the 60 mg dose aren't yet mature, since six patients were still responding at the time of data cutoff.
Responses were seen in both hormone receptor-positive and triple-negative breast cancer patients, and the drug's activity was consistent across specific mutation-defined subgroups.
"Saruparib delivered promising efficacy with deep and durable responses," Yap said. "It has superior efficacy compared to the approved PARP inhibitors and is conveniently administered as a once-daily dose." This could potentially allow patients treated with saruparib to remain on treatment longer at an optimal dose, he noted.
"The efficacy was profound," echoed Patricia LoRusso, associate center director for innovative medicine at Yale Cancer Center, during a discussion of the PETRA results on Monday.
In an exploratory analysis, investigators looked at patients' circulating tumor DNA and found that 64 percent of ctDNA-evaluable patients on the 60 mg saruparib dose had a molecular response, defined as at least a 50 percent mean decrease in variant allele frequency. "ctDNA molecular responses correlate with improved progression-free survival, and therefore we believe that ctDNA kinetics is a promising early treatment response biomarker in patients with breast cancer," he said.
As a next step, AstraZeneca is studying saruparib in a Phase III clinical trial, dubbed EvoPAR-PR01, in which HRR-mutant prostate cancer patients are randomized to receive either saruparib plus hormone therapy or placebo plus hormone therapy. This trial is using the 60 mg dose of saruparib determined as optimal in the PETRA trial.
As the investigational PARP1 inhibitor moves into other trials, it raises several questions about the PARP inhibitor landscape at large, LoRusso said during her discussion. For instance, can a selective PARP1 inhibitor be considered a "second generation" of already available PARP inhibitors? Or do PARP1 agents comprise a new drug class altogether? Given the observed differences in toxicity and the potential for better efficacy with saruparib, she suggested that PARP1 drugs could be a new class of agents.
Saruparib isn't the only PARP1 agent in development. At the AACR annual meeting alone, LoRusso noted that researchers were presenting data on at least eight different PARP1 selective inhibitors, though some are still in much earlier stages of development. Internationally, there may be many more PARP1 programs underway, she added.
It remains to be seen whether any of these other agents will have a leg up over saruparib, and although the data are still very early, LoRusso pointed to another PARP1 agent AstraZeneca is developing, AZD9574, that appears to penetrate the blood-brain barrier in animal models. If those results play out similarly in human clinical trials, she suggested that drug might be best suited for cancer types that commonly metastasize to the brain.
In the future, LoRusso also said investigators will need to study whether these drugs can be combined with other agents like chemotherapy, and if so, whether that's an ideal strategy. "We need to think about the biology of the drugs that we're using in combinations," she said.
Finally, a key question that Yap and his colleagues are still trying to figure out is why a patient who's refractory to first-generation PARP1/2 inhibitors might respond to a PARP1 drug like saruparib.
"It's something I've been scratching my head on," Yap said during a press conference Monday morning. "One could argue we have a better drug here … but it could be multifactorial."