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TAPUR Results Support Lynparza's Activity in BRCA1/2-Mutant Pancreatic Cancer


NEW YORK – Results from a cohort of the Targeted Agent and Profiling Utilization Registry (TAPUR) basket trial found that AstraZeneca's PARP inhibitor Lynparza (olaparib) showed activity as a second-line or later treatment for advanced pancreatic cancer with BRCA1/2 mutations.

The results, published in JCO Precision Oncology in February, included data from 28 evaluable patients with previously treated germline or somatic BRCA1/2-mutant advanced pancreatic cancer. The trial ran between 2016 and 2019 and preceded Lynparza's approval in 2019 as a maintenance therapy after first-line platinum-based chemotherapy treatment for patients with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic cancer.

The aim of the overall TAPUR study was to evaluate whether already-approved targeted therapies were effective in other molecularly defined cancers. The basket trial had more than a dozen treatment arms evaluating targeted therapies outside of their approved indications and some in a tumor agnostic setting.

In the Lynparza TAPUR results, two patients achieved a complete response on Lynparza and another three achieved a partial response, resulting in an overall response rate of 18 percent. Three patients also experienced stable disease on the treatment, and the disease control rate, inclusive of patients who responded and had stable disease, was 31 percent.

The median progression-free survival was eight weeks, and the median overall survival was 38 weeks.

Eugene Ahn, lead author of the study and deputy medical director of clinical research at City of Hope Atlanta, Chicago, and Phoenix, noted that one patient with a complete response on Lynparza was continuing on treatment and had not progressed after more than four years.

Responders included patients with only BRCA1 and with only BRCA2 mutations. Among patients who received prior platinum-containing chemotherapy, two experienced a complete response, one experienced a partial response, and two experienced stable disease for 16 weeks or more.

Ahn said that these results "further validate [Lynparza's] approval" in pancreatic cancer based on the Phase III POLO study. However, he added that the TAPUR study and the POLO trial had some notable differences in patient characteristics that suggest the drug may work for a slightly wider patient population than the current indication reflects.

"The studies that led to approval specifically homed in on patients who already had platinum therapy, and we know that those who get platinum therapy are more likely to have a response with PARP inhibitors," he explained, adding that the POLO study also only enrolled patients with a germline variant, while TAPUR included patients with either germline or somatic mutations. "We generally know germline BRCA1/2 patients are more likely to have a response."

"PARP inhibitors are approved for a really pre-selected group that had a very good response and durable remission with platinum-based chemotherapy," Ahn said. "In [the POLO] patient population, we would expect to see a higher response rate because they're more pre-selected."

While the TAPUR cohort is not large enough to support a potential approval expansion, Ahn said it still suggests that PARP inhibitors like Lynparza could be an option for a less selective patient population than the current approval for only pancreatic cancer patients with a germline BRCA1/2 mutation who responded to platinum chemotherapy for at least 16 weeks.

"Patients want more options besides chemotherapy," he said. "There's a large patient demand for looking at PARP inhibitors in a less selected [population]. Our study does validate [prior results] even in a less selected patient population, and we're still seeing reasonable response rates."

Another PARP inhibitor, Clovis Oncology's Rubraca (rucaparib) has also shown activity in a slightly wider pancreatic cancer patient population. In results from an investigator-sponsored study presented in 2021, Rubraca showed activity in advanced pancreatic cancer patients with germline or somatic mutations in BRCA1, BRCA2, or PALB2. However, at the time, a Clovis spokesperson said the company did not plan to pursue further research of Rubraca in pancreatic cancer.

AstraZeneca is also studying its next-generation PARP1 inhibitor AZD5305 in a Phase I/II trial in advanced breast, ovarian, prostate, or pancreatic cancer patients bearing germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations. In results from that trial, presented in 2022, AZD5305 showed activity across multiple cancers, with a 25 percent overall response rate, and in patients who had received a variety of prior therapies. GlaxoSmithKline is also exploring its PARP inhibitor Zejula (niraparib) across multiple cancers, including pancreatic cancer with germline or somatic PALB2 mutations in a Phase II trial.

While Ahn noted that the TAPUR results don't seem to show a large benefit, as the study reported only a 31 percent disease control rate, the drug could be an improvement for pancreatic cancer patients who have few treatment options.

"We know that pancreatic cancer is one of the worst prognosis for metastatic cancer," Ahn said. "Treatment options are very limited. Usually you have chemotherapy and PARP inhibitors if [the patient] has the BRCA1/2 mutation, but in essence, that's it. These kind of outcomes were unheard of in salvage therapy for pancreatic cancer. Although the percentages don't seem large, certainly the effect size for those two patients [with durable responses] has been huge."

Ahn also stressed the importance of genomic sequencing for pancreatic cancer patients, especially germline testing. Previous studies have also supported the value of germline testing in pancreatic cancer. A study from Moffitt Cancer Center last year evaluated the utility of a therapeutic panel that tested for germline variants in a larger number of genes. In that pilot study, half of patients with a targetable genetic variant received a precision therapy.

Ahn added that he and his colleagues always recommend doing genomic testing, as patients may not know whether they have a germline variant for cancer risk and testing results may open up more treatment options.

"If the patient never had genomics, they might never have known if they're an eligible candidate for PARP inhibitors," Ahn said. "What we learned from this case is that if the genomic [variant] is there, it doesn't matter what the cancer is, the drug still works, and that's a common theme we're seeing for a lot of the drugs we're studying on the TAPUR study."