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Treatment With Less Toxic Rubraca in Molecularly-Defined Pancreatic Cancer Subset Proposed at AACR


ATLANTA (GenomeWeb) – Based on early but encouraging data presented today at the American Association for Cancer Research annual meeting, physician scientists proposed changing the treatment paradigm for advanced pancreatic cancer patients with mutations in BRCA1, BRCA2, or PALB2 genes.

"We are proposing a novel strategy to treat these patients, for whom the standard of care is indefinite chemotherapy until progression, decline, or death," said Kim Reiss Binder, assistant professor of medicine of the hematology and oncology division within The Hospital of the University of Pennsylvania. "What if we can find the right people? What if we can find a group for whom that intensive, toxic period of chemo is used as an induction, and once the disease stabilizes, we continue with a less toxic maintenance option?"

Cancer patients who have BRCA1/2 mutations respond well to platinum-based chemotherapy and possibly also PARP inhibitors. The standard of care for advanced pancreatic cancer patients is chemotherapy for the rest of their lives. Between 5 percent and 8 percent of pancreatic cancer patients harbor pathogenic mutations in these and other genes, such as PALB2, involved in DNA damage repair through homologous recombination (HR) and respond particularly well to platinum-based chemotherapy.

"Here's the problem. [These patients] do very, very well," said Binder. "They can be on chemotherapy for months, sometimes years, and the only thing we can do in the advanced disease setting standard of care right now is continuous and indefinite chemotherapy." But prolonged chemotherapy allows toxicity to build up in patients and diminishes their quality of life.  

Meanwhile, PARP inhibitors, such as Clovis Oncology's rucaparib (Rubraca) and AstraZeneca's olaparib (Lynparza), are now commercially available treatment options for advanced ovarian and breast cancer patients with germline BRCA1/2 mutations. These drugs have shown early activity in pancreatic cancer patients with these mutations and they also cause far less toxicity in patients than chemotherapy.

Binder, Susan Domchek, and colleagues from the University of Pennsylvania, decided to test out a new treatment paradigm where advanced pancreatic cancer patients with mutations in BRCA1/2 or PALB2 would receive platinum chemotherapy for a period of time and then go on to receive a lower toxicity PARP inhibitor as maintenance treatment.

The patients in the study have to receive platinum-based chemo for at least four months without progressing in order to be eligible for the trial, at which time they would stop chemo and start Clovis' rucaparib and be followed for progression-free survival. Researchers have aimed to enroll 42 patients in this ongoing Phase II study and so far 30 have joined.

At the meeting, Binder presented interim data reflecting the experiences of 19 patients. Study participants could have been tested by any CLIA certified lab for their mutation status in BRCA1/2, or PALB2. Seventeen patients had pathogenic germline variants in these genes, and two patients had somatic mutations detected by a lab that experts at the University of Pennsylvania evaluated again to make sure was pathogenic.

None of the patients in this cohort experienced serious toxicities. Patients experienced fatigue and diarrhea, and one patient reduced the drug dose because of nausea. "This highlights how incredibly tolerable this drug is," Binder said.

Manish Shah, director of the Gastrointestinal Oncology Program at Weill Cornell Medicine and New York-Presbyterian, wasn't involved in this study, but agreed upon seeing the preliminary data that the toxicity profile of rucaparib does seem far better than chemotherapy. Platinum-based chemotherapies can damage the kidneys, heart, and central nervous system, and cause hearing loss, bone marrow suppression, and low white cell count. "The opportunity to switch to an active maintenance drug could significantly limit toxicity and is quite worthwhile," Shah told GenomeWeb.

At a median follow-up of around 8 months, median progression-free survival was 9.1 months from the time patients started rucaparib. Median overall survival had not been reached in these patients at the time of median follow up.

Seventeen patients in the study experienced stable disease or saw their tumors shrink. Two patients progressed in the trial, but a dozen patients are still on the study. Two patients had been in the study for over a year.

Binder's group saw responses in patients with germline BRCA1/2 and PALB2 mutations, and one patient with a somatic BRCA2 mutation. One patient had a complete response, but it took six months to start to see her tumors shrink and eight months for the lesion to reduce by 40 percent.

"These responses can be slow," she said. "If you see the responses at the beginning, you think it's just delayed effect from platinum chemotherapy. … But, for the patient who reached a complete response for 32 weeks and for a couple of the others, it's four to six months before they trickled down to an actual response, which suggests it's really the PARP inhibitor doing its work rather than you're just happening to catch the tail end of their chemo."

There is precedence for this type of treatment paradigm using PARP inhibitors as maintenance treatment in ovarian cancer. The FDA last year approved AstraZeneca/Merck's olaparib (Lynparza) as first-line maintenance therapy for advanced ovarian cancer patients with BRCA1/2 mutations who have responded to platinum-based chemotherapy. The approval was based on data from the SOLO-1 trial in which patients receiving olaparib hadn't reached median progression-free survival at the time of data analysis, and researchers estimated that olaparib-treated patients could have median progression-free survival that's three years longer than the placebo group.

Binder noted that SOLO-1 also included a comparison of quality of life between the olaparib and placebo arms, and there was no difference. "I thought that was fabulous. If we can do that for people that would be wonderful," she said. "And, we can use some of these successes to model after."

AstraZeneca and Merck are also working on advancing olaparib as first-line maintenance treatment for patients with germline BRCA-mutated metastatic pancreatic cancer, and have announced top-line data from the randomized POLO study as support. Myriad Genetics' companion diagnostic was used to identify BRCA mutations in patients enrolled in this study, and the company has said it will submit a supplementary premarket approval application for BRACAnalysis CDx for this indication.

Clovis will likely pursue a similar path for rucaparib. Based on this interim analysis and data from another study in pancreatic cancer, the drugmaker said this week it will explore expanding rucaparib's label to this new maintenance indication.

"It is becoming clear that PARP inhibitors may offer a much-needed new treatment option for the physicians and patients who are facing the challenge of pancreatic cancer," Clovis CEO Patrick Mahaffy said in a statement. "Based on the encouraging early findings from this investigator-initiated study, as well as the findings from our own RUCAPANC trial of Rubraca in pancreatic cancer, we are evaluating a potential clinical and regulatory path forward for Rubraca in the treatment of pancreatic cancer." The company will provide more details later this year.

The aim of the study presented at the meeting was to demonstrate that rucaparib-based maintenance treatment wouldn't be worse than the standard of care with chemo in pancreatic cancer patients, but that it would significantly improve their' quality of life. Binder ended the presentation with pictures of patients in the study riding a tractor, shopping for flowers, celebrating an anniversary on the beach, and teaching a painting class in Paris — things they couldn't do before getting maintenance treatment with rucaparib.

"This is a very hopeful prospect," said William Nelson, director of the Sidney Kimmel Comprehensive Cancer at Johns Hopkins University, reflecting on the interim data. "If we can develop a drug that attacks something related to the cancer it probably will get [to cancer cells] and if it's effective and we can do it with reasonable tolerability, quality of life can be improved."

"The study is very compelling and encouraging," Shah agreed, but he said that a larger, randomized study is likely needed before this becomes practice changing.

This study naturally raises the question as to whether pancreatic cancer patients with mutations in other DNA repair genes, such as ATM and CHEK2, will similarly benefit from rucaparib. Binder acknowledged this possibility, but said more research is needed to make sure that mutations in these genes behave similarly to BRCA1/2 and PALB2 mutations in pancreatic cancer.

Binder and colleagues' proposed change in the treatment paradigm for BRCA1-, BRCA2-, or PALB2-mutated advanced pancreatic cancer patients comes as the National Comprehensive Cancer Network last year updated its guidelines to recommend germline genetic testing for BRCA1/2 and other hereditary cancer risk genes for all pancreatic cancer patients. Guidelines are also supportive of somatic testing in this setting. Having mutations in these genes can impact screening and treatment strategies for the patient but can also provide important information that leads to family members getting tested.

Many academic centers, including Weill Cornell, have already been testing pancreatic cancer patients for germline mutations, Shah said. "But it will likely take some time for general oncologists across the country to begin to do this."