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Accreditation/ Credit Designation

Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

These activites are not approved for AMA PRA Category 1 Credit™.

Acknowledgment of Commercial Support

This activity is supported by educational grants from Clovis Oncology Inc., Foundation Medicine Inc., and Tesaro Inc.

Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction PER Pulse™ Recap

PER Pulse Recap

PER Pulse™ Recap



1 of 3
PER Pulse Recap

Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction

The online continuing medical education activity Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction, presented in conjunction with the 34th Annual Chemotherapy Foundation Symposium, featured the following experts describing the role of poly(ADP-ribose) polymerase (PARP) inhibition in ovarian cancer: Maurie Markman, MD; Michael J. Birrer, MD, PhD; Michael Bookman, MD; and Mark E. Robson, MD. This program featured engaging discussion about the current and emerging uses of PARP inhibitors in ovarian cancer. This first of 3 PER Pulse™ Recaps reviews the rationale for PARP inhibition in women with ovarian cancer.

PARP is actually a family of proteins involved in DNA damage repair, recognizing and repairing single-stranded DNA breaks. Dr. Birrer explained that the disruption of this repair with PARP inhibitors leads to double-stranded DNA breaks, which are lethal events unless they can be repaired. The cell accomplishes double-stranded DNA repair using a repair complex, which contains BRCA1, BRCA2, and a number of other proteins. Mutations in proteins within this complex can lead to disruption of this repair process, which is called homologous recombination. Therefore, ovarian cancers with BRCA1 or BRCA2 mutations should be particularly susceptible to PARP inhibition. Moreover, cancers showing a deficiency in homologous recombination for any reason, called homologous recombination deficiency (HRD), should also demonstrate susceptibility to PARP inhibitors.

In fact, both of these hypotheses are supported by clinical data. In the olaparib pivotal trial, single-agent olaparib produced a 34% response rate, a median duration of response of 7.9 months, and a progression-free survival (PFS) hazard ratio (HR) of 0.18 in patients with heavily pretreated BRCA-mutated ovarian cancer. In the NOVA study in recurrent ovarian cancer, Dr. Robson explained that a PFS benefit of niraparib was reported not only in BRCA-mutated disease (HR, 0.27), but also in BRCA wild-type, HRD-positive tumors (HR, 0.38). Ovarian cancer is an attractive cancer type in which to study PARP inhibitors because a significant portion of these cancers—10% to 15%--have BRCA mutations, and even more are HRD-positive.

Dr. Bookman pointed out that the mechanism of PARP inhibition also provides a rationale to combine PARP inhibitors with chemotherapy or radiation therapy, both of which increase DNA damage and cell stress, which may increase sensitivity of cells to PARP inhibition. Clinical studies are currently under way to study PARP inhibitors in combination with platinum agents in ovarian cancer.

For additional commentary about this topic and Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction, please visit www.gotoper.com.



2 of 3
PER Pulse™ Recap

Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction

The online continuing medical education activity Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction, presented in conjunction with the 34th Annual Chemotherapy Foundation Symposium, featured the following experts describing the role of poly(ADP-ribose) polymerase (PARP) inhibition in ovarian cancer: Maurie Markman, MD; Michael J. Birrer, MD, PhD; Michael Bookman, MD; and Mark E. Robson, MD. This program featured engaging discussion about the current and emerging uses of PARP inhibitors in ovarian cancer. This second of 3 PER Pulse Recaps describes genetic testing and biomarkers associated with PARP inhibition.

PARP inhibitors clearly respond strongly against the 10% to 15% of tumors harboring BRCA mutations, although Dr. Birrer discussed laboratory data showing that not all BRCA mutations produce equal sensitivity to PARP inhibition. Some mutations only partially inactivate the protein, with these proteins retaining some wild-type activity. He suggested that cancers with these particular mutations may be less susceptible to PARP inhibitors.

BRCAness, or the sharing of molecular features of BRCA-mutated tumors, may be just as important to patient selection as BRCA mutations themselves, and may expand PARP inhibitors’ eligible patient population considerably. Dr. Robson clarified this concept by explaining that the PARP-sensitive phenotype is currently manifested most clearly in patients with BRCA-mutated tumors, but that this phenotype is also linked broadly to tumors with homologous recombination deficiency (HRD). There is interest in determining whether mutations in other proteins important to homologous recombination, such as RAD51 and Palb2, produce the same PARP-sensitive phenotype; however, there are clinical challenges in completing trials to answer all of these questions.

Dr. Robson also discussed the results of the placebo-controlled NOVA trial, in which a subset of patients whose tumors were HRD-positive, but germline BRCA wild-type, achieved an intermediate response to PARP inhibition with niraparib. He explained that even those patients with BRCA wild-type, HRD-negative disease derived a significant, albeit modest, benefit from PARP inhibition, leading to the question of whether grading PARP sensitivity is even clinically relevant, since physicians are likely to prescribe a PARP inhibitor for patients even if the clinical benefit is modest.

Finally, Dr. Birrer highlighted the ARIEL2 data of rucaparib, which was recently filed with the US Food and Drug Administration (FDA), because this study demonstrated that patients with somatic BRCA mutations had similar PARP sensitivity to those patients with germline BRCA mutations. He suggested that somatic mutations would become a part of rucaparib’s label, which it did when rucaparib was approved by the FDA in December 2016 for the treatment of patients with advanced ovarian cancer with either germline or somatic BRCA mutations.
For additional commentary about this topic and Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction, please visit www.gotoper.com.


3 of 3
PER Pulse™ Recap

Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction

The online continuing medical education activity Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction, presented in conjunction with the 34th Annual Chemotherapy Foundation Symposium, featured the following experts describing the role of poly(ADP-ribose) polymerase (PARP) inhibition in ovarian cancer: Maurie Markman, MD; Michael J. Birrer, MD, PhD; Michael Bookman, MD; and Mark E. Robson, MD. This program featured engaging discussion about the current and emerging uses of PARP inhibitors in ovarian cancer. This third of 3 PER Pulse Recaps discusses current and emerging clinical uses of PARP inhibitors in ovarian cancer.

Dr. Bookman reviewed the status of olaparib, stating that although it was originally intended to be used for maintenance therapy, it received US Food and Drug Administration (FDA) approval in women with heavily pretreated BRCA-mutated ovarian cancer. Dr. Birrer pointed out that niraparib became the first PARP inhibitor to file for a maintenance therapy indication for ovarian cancer in the United States, based on the results of its NOVA study. He also said he expected rucaparib, another PARP inhibitor with a proposed indication in relapsed disease, to receive FDA approval based on the results of its pivotal ARIEL2 trial, which it received in December 2016. With this indication, rucaparib became the first PARP inhibitor to be approved by the FDA for patients with either germline or somatic BRCA mutations.

Dr. Bookman discussed how important it will be to manage the toxicities of PARP inhibitors, particularly if they are used indefinitely in the maintenance setting in patients without disease-related symptoms. He raised both dose and schedule as potential variables to manipulate in order to reduce toxicities, particularly since he believes the PARP inhibitor dosages currently used may be higher than is optimal. Both Dr. Bookman and Dr. Birrer suggested that perhaps intermittent dosing schedules would improve tolerability of PARP inhibitors. Although fatigue, nausea/vomiting, and myelosuppression were mentioned as common toxicities with PARP inhibitors, the faculty agreed that these agents were well tolerated overall.

The faculty also had a discussion on the theoretical risk of myelodysplasia and leukemia with PARP inhibition, owing both to its mechanism of action and the fact that patients receiving PARP inhibitors have already received prior therapy with DNA-damaging platinum therapy. Dr. Birrer called the data thus far reassuring but cautioned that long-term data are needed, particularly if these agents will be used in the maintenance setting. Dr. Markman agreed that the risk appears low, but it cannot be ignored. Dr. Bookman said that data are accumulating which show that the risk of myelodysplasia is not increased, at least to the level that can be measured in current clinical trials.
For additional commentary about this topic and Medical Crossfire®: The Expanding Role of PARP Inhibitors in the Treatment of Ovarian Cancers – Current Strategies and Future Direction, please visit www.gotoper.com.





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