Ovarian cancer drug shows promise in pancreatic cancer patients with BRCA mutation

In continuation of my update on Rucaparib

A targeted therapy that has shown its power in fighting ovarian cancer in women including those with BRCA1 and BRCA2 mutations may also help patients with aggressive pancreatic cancer who harbor these mutations and have few or no other treatment options. An international team of researchers led by the Perelman School of Medicine and the Basser Center for BRCA at the University of Pennsylvania reported their findings this week in JCO Precision Oncology.

The drug, PARP inhibitor rucaparib, which was approved by the U.S. Food and Drug Administration (FDA) last month for the treatment of women with ovarian cancer who have recurrent disease or received prior therapies, showed its clinical benefit in previously treated pancreatic patients with BRCA mutations in a phase II clinical trial. Of the 19 patients treated, four had responses and two additional patients had stable disease.

"These results not only point us in a new treatment direction to further investigate for patients with pancreatic cancers, but it also reinforces the clinical significance of the BRCA genes beyond ovarian and breast cancer and the utility of PARP inhibitors in other cancers," said Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania.

PARP—poly (ADP-ribose) polymerase—is an enzyme used by healthy cells to repair themselves. However, cancer cells also use PARP to repair DNA damage, thus extending their growth and possible lethality. Preliminary results from the study, which included patients from seven centers around the globe, were presented at the annual meeting of the American Society of Clinical Oncology in 2016. These latest findings represent the full study.

Pancreatic cancer, which is often caught in later, more aggressive stages, is projected to become the second leading cause of cancer death by 2020, emphasizing the need for a larger and more effective arsenal of treatments to combat the disease. Only about 32 percent of patients respond to a first line of chemotherapy, and less than 20 percent who don't respond to a first line of chemotherapy end up responding to a second.

This underscores the importance of looking outside of chemotherapy options, the authors said, particularly in patients with targetable mutations, like BRCA.

Importantly, Domchek said, none of the patients who benefited from rucaparib had tumors that had progressed on a prior platinum-based chemotherapy, suggesting a potential role for rucaparib as an earlier treatment for patients whose tumors are not resistant to such treatments.

Rucaparib is a PARP inhibitor shown to be an effective therapy in ovarian cancers with BRCA 1/2 mutations. In 2016, the drug was approved by the FDA for women with BRCA-associated ovarian cancer who received two or more prior chemotherapies. And in April 2018, the approval was extended to women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are having a complete or partial response to platinum-based chemotherapies.

The success of rucaparib in ovarian cancers is what prompted the clinical study in pancreatic patients with the same mutation. About nine percent of pancreatic patients have BRCA/2 mutation associated pancreatic cancer.

Overall, a clinical benefit was observed in 32 percent of patients (6/19) treated with rucaparib, and 45 percent in patients (4/9) who had received only one prior chemotherapy for locally advanced or metastatic disease. Nine patients had progressive disease, and three were not evaluable for response. The objective confirmed response rate, the primary endpoint for the study, was 16 percent (3/19).

The trial included 11 men and eight women, with a median age of 57. Twenty-one percent of the patients had BRCA1mutation-associated pancreatic cancer, while 79 percent were associated with BRCA2 mutations.

"Consideration should be given to use of this therapy for treatment of patients whose tumors have not progressed on prior platinum therapy," the authors wrote. "Future studies should focus on better understand the sequencing of PARP inhibitor treatment and potential maintenance therapy, as well as potential predictors of resistance to therapy."

Rubraca (rucaparib) Approved in the U.S. as Maintenance Treatment of Recurrent Ovarian Cancer

In continuation of my update on Rucaparib

Clovis Oncology, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved Rubraca (rucaparib) tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. FDA granted regular approval for Rubraca in this second, broader and earlier-line indication on a priority review timeline based on positive data from the phase 3 ARIEL3 clinical trial. Biomarker testing is not required for patients to be prescribed Rubraca in this maintenance treatment indication. Warnings and precautions include Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and embryo-fetal toxicity.

In addition to granting Rubraca approval in this second indication, the FDA converted the approval of the initial treatment indication from accelerated to regular approval.

“Rubraca provided statistically-significant improvement in PFS versus placebo to all patients, regardless of BRCA mutation status,” said Robert L. Coleman, MD, Professor & Executive Director, Cancer Network Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the Principal Investigators in the ARIEL3 clinical trial program. “Both the efficacy and safety results from the ARIEL3 study reinforce the important role of Rubraca in the treatment of recurrent ovarian cancer and expands the treatment options for patients and physicians battling this disease.”

“This FDA approval provides a meaningful advancement for the treatment of women with recurrent ovarian cancer, offering them the potential to reduce their risk of disease progression following platinum-based chemotherapy,” said Patrick J. Mahaffy, CEO and President of Clovis Oncology. “We are grateful that the FDA expedited review of this maintenance treatment indication, so that physicians can begin offering it to appropriate patients beginning today.”

On February 28, 2018, Rubraca was added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Ovarian Cancer, as maintenance therapy for patients with platinum-sensitive epithelial ovarian, fallopian tube and primary peritoneal cancer who are in partial or complete response after completion of two or more lines of platinum-based therapy. The NCCN designated Rubraca as a category 2A treatment.

NCCN is a not-for-profit alliance that includes 27 of the world’s leading cancer institutions. The NCCN Guidelines document evidence-based, consensus-driven management to ensure that all patients receive preventive, diagnostic, treatment, and supportive services that are most likely to lead to optimal outcomes.[1]

In December 2017, FDA accepted the Rubraca supplemental New Drug Application (sNDA) application and granted priority review status. Priority review designation is granted to proposed medicines that FDA has determined have the potential, if approved, to offer a significant improvement in the safety or effectiveness for the treatment, prevention or diagnosis of a serious condition when compared to standard applications. The Rubraca maintenance treatment approval is based on positive results from the ARIEL3 study, which evaluated Rubraca in the ovarian cancer maintenance-treatment setting among three populations: 1) BRCA mutant (BRCAmut+) 2) HRD positive inclusive of BRCAmut+ and, 3) all patients treated in ARIEL3. The study enrolled a total of 564 patients.

ARIEL3 successfully achieved both its primary and key secondary endpoints, extending investigator assessed progression-free survival (PFS) versus placebo in all patients treated, regardless of BRCA status.

Clovis announced topline results from the ARIEL3 clinical trial in June 2017. Additional data from the trial were presented at the 2017 European Society for Medical Oncology (ESMO) Annual Conference in Madrid, Spain, and subsequently published in The Lancet.

“The FDA approval of Rubraca in the maintenance treatment setting is an important milestone for physicians and their patients with recurrent ovarian cancer because it offers them greater flexibility to use this novel PARP inhibitor, which has demonstrated significant clinical efficacy and has been well received in practice,” said Professor Jonathan Ledermann, MD, Professor of Medical Oncology, Clinical Director, UCL Cancer Institute, and European and the rest of world Principal Investigator for the ARIEL3 study. “This will enable physicians to offer Rubraca to more women with platinum-sensitive, recurrent ovarian cancer.”

"Tens of thousands of women will battle ovarian cancer every year,” said David Barley, Chief Executive Officer, National Ovarian Cancer Coalition. “We need therapies that provide clinically meaningful improvements in reducing the risk of disease progression, among women with recurrent disease."

The safety evaluation of Rubraca 600 mg twice daily as monotherapy for maintenance treatment is based on data from 561 patients with recurrent ovarian cancer treated in the ARIEL3 trial. The safety and tolerability of Rubraca observed in this study was consistent with the previous Rubraca studies. The most common adverse reactions (greater than or equal to 20% of patients; CTCAE Grade 1-4) were nausea, fatigue/asthenia, abdominal pain/distention, rash, dysgeusia, anemia, AST/ALT elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/upper respiratory tract infection, stomatitis, decreased appetite and neutropenia. The most common laboratory abnormalities (greater than or equal to 25% of patients; CTCAE Grade 1-4) were increase in creatinine, decrease in hemoglobin, increase in cholesterol, increase in alanine aminotransferase (ALT), increase in increase in aspartate aminotransferase (AST), decrease in platelets, decrease in leukocytes, decrease in neutrophils, increase in alkaline phosphatase and decrease in lymphocytes. The majority of adverse reactions and laboratory abnormalities were Grade 1-2.

FDA awards accelerated approval to new ovarian cancer drug

In continuation of my update on Rubraca                                         

The U.S. Food and Drug Administration today granted accelerated approval to Rubraca (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test.

"Today's approval is another example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient's genes," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and acting director of the FDA's Oncology Center of Excellence. "Women with these gene abnormalities who have tried at least two chemotherapy treatments for their ovarian cancer now have an additional treatment option."

The National Cancer Institute estimates that 22,280 women will be diagnosed with ovarian cancer in 2016 and an estimated 14,240 will die of this disease. Approximately 15 to 20 percent of patients with ovarian cancer have a BRCA gene mutation.

BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers. Rubraca is a poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.

Today, the FDA also approved the FoundationFocus CDxBRCA companion diagnostic for use with Rubraca, which is the first next-generation-sequencing (NGS)-based companion diagnostic approved by the agency. The NGS test detects the presence of deleterious BRCA gene mutations in the tumor tissue of ovarian cancer patients. If one or more of the mutations are detected, the patient may be eligible for treatment with Rubraca.

The safety and efficacy of Rubraca were studied in two, single-arm clinical trials involving 106 participants with BRCA-mutated advanced ovarian cancer who had been treated with two or more chemotherapy regimens. BRCA gene mutations were confirmed in 96 percent of tested trial participants with available tumor tissue using the FoundationFocus CDxBRCA companion diagnostic. The trials measured the percentage of participants who experienced complete or partial shrinkage of their tumors (overall response rate). Fifty-four percent of the participants who received Rubraca in the trials experienced complete or partial shrinkage of their tumors lasting a median of 9.2 months.

Common side effects of Rubraca include nausea, fatigue, vomiting, low levels of red blood cells (anemia), abdominal pain, unusual taste sensation (dysgeusia), constipation, decreased appetite, diarrhea, low levels of blood platelets (thrombocytopenia) and trouble breathing (dyspnea). Rubraca is associated with serious risks, such as bone marrow problems (myelodysplastic syndrome), a type of cancer of the blood called acute myeloid leukemia and fetal harm.

The agency approved Rubraca under its accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease or condition based on clinical data showing the drug has an effect on a surrogate (substitute) endpoint that is reasonably likely to predict clinical benefit. The sponsor is continuing to study this drug in patients with advanced ovarian cancer who have BRCA gene mutations and in patients with other types of ovarian cancer. The FDA also granted the Rubraca application breakthrough therapy designation and priority review status. Rubraca also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.

Rubraca is marketed by Clovis Oncology, Inc. based in Boulder, Colorado. The FoundationFocus CDxBRCA companion diagnostic is marketed by Foundation Medicine, Inc. of Cambridge, Massachusetts.

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

The targeted therapy rucaparib, which has demonstrated robust clinical activity in ovarian cancer patients with a BRCA mutation, also showed promise in previously treated pancreatic cancer patients with the mutation, according to results from a phase II clinical study presented by Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, at the American Society of Clinical Oncology (ASCO) Annual Meeting. (Abstract # 4110).

rucaparib

Overall, a clinical benefit was observed in 32 percent of patients (6 of 19) treated with rucaparib. Of the 19 pancreatic patients, one had a complete response and two had partial responses, while four patients had stable disease. The objective response rate, the primary endpoint for the study, was 16 percent (3 of 19).

"These results are encouraging and further demonstrate the clinical significance of the BRCA cancer genes outside of breast and ovarian, and not just in women," Domchek said. "Importantly, it points us to a potential new treatment avenue for pancreatic cancer, an aggressive disease that's often caught in the later stages. Though smaller in number, some patients with advanced disease and carrying a BRCA mutation may benefit from the same targeted therapy being used today in the clinic to successfully treat some ovarian cancer patients."

Given the poor prognosis and limited treatment options in pancreatic cancer, new therapies to combat the disease are desperately needed: Earlier this year, the American Cancer Society reported that it is estimated that in 2016, nearly 42,000 people will die from the disease, surpassing the number of deaths from breast cancer by more than 1,000.

Recent studies have shown that rucaparib, a PARP inhibitor, effectively treats patients with platinum-sensitive, relapsed, high-grade ovarian cancer harboring a BRCA mutation. In a study presented at ASCO in 2015, researchers showed that treatment resulted in a 69 percent RECIST response rate in these patients. In April 2015, it received a U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation. The FDA's designation, created in 2012, is intended to expedite the development and review of new medicines - both drugs and biologic agents - that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The success in ovarian patients prompted a clinical study in pancreatic patients with the same mutation--about nine percent of pancreatic patients are BRCA1/BRCA2 positive.

The team enrolled participants with measurable, relapsed disease who received one to three prior rounds of chemotherapy for locally advanced or metastatic cancer. The trial included 11 male and eight female patients, with a median age of 57. Twenty-one percent of the patients tested positive for the BRCA1 mutation, while 79 percent tested positive for BRCA2.

The disease control rate (defined as partial response or stable disease for more than 12 weeks) for all patients was 32 percent (6 of the 19 patients) and 50 percent (three of six patients) in patients who received one prior line of chemotherapy. Four patients had stable disease, nine patients had progressive disease, and three were not evaluable for response. One patient was on the drug for 72 weeks and is continuing to receive the drug. The drug had an acceptable safety profile. Common treatment-emergent side effects included nausea (63 percent) and anemia (47 percent).

All patients who responded received only one prior line of chemotherapy therapy, suggesting that the drug may be an option earlier in the treatment course.

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation