Kathleen Moore, MD, director, Oklahoma TSET Phase I Program, and associate professor, Section of Gynecologic Oncology, at Stephenson Cancer Center, discusses treatment options for patients with ovarian cancer who progress on a PARP inhibitor.

If a patient progresses on frontline maintenance therapy with a PARP inhibitor, the best indicator of subsequent response to PARP is still platinum sensitivity, says Moore. Therefore, if treating a patient who re-responded to platinum-based therapy, PARP inhibition as maintenance treatment may be tried again.

In terms of mechanisms of resistance, investigators demonstrated that patients in the phase II ARIEL2 trial who harbored 

 reversion mutations in their circulating tumor DNA did not respond to rucaparib (Rubraca). These patients were PARP inhibitor—naïve, but they previously received platinum-based therapy, says Moore.

If a reversion mutation could be identified up front, it could indicate whether or not the patient should be put on a PARP inhibitor, a clinical trial with an alternative agent, or bevacizumab (Avastin). However, a commercially available assay has yet to be developed in that regard, concludes Moore.

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Kathleen Moore, MD, director, Oklahoma TSET Phase I Program, and associate professor, Section of Gynecologic Oncology, Stephenson Cancer Center, discusses treatment for patients with ovarian cancer who progress on a PARP inhibitor.

Dr. Moore on Treatment for Patients With Ovarian Cancer Who Develop Resistance to PARP Inhibitors

Kathleen Moore, MD, director, Oklahoma TSET Phase I Program, and associate professor, Section of Gynecologic Oncology, Stephenson Cancer Center, discusses research evaluating repeat exposure to PARP inhibition in patients with platinum-sensitive ovarian cancer.

In the prospective phase II Evolve study, Stephanie Lheureux, MD, and her colleagues took women who had progressed on a prior PARP inhibitor and evaluated one of the reported mechanisms of acquired resistance to PARP with combination therapy. One of the ways that patients develop resistance to PARP inhibition is upregulation of a pathway that restores homologous recombination proficiency (HRP). One of those pathways is VEGF.

Therefore, researchers believe that the combination of a PARP inhibitor with an antiangiogenic agent like bevacizumab (Avastin) or the TKI cediranib could overcome that acquired resistance, says Moore. Evolve was a small, translational science—driven study, in which investigators evaluated mechanisms of escape in platinum-sensitive, platinum-resistant, and unknown patients. Among 10 evaluable patients in each cohort, investigators noted some responses. Further data will be very important to apply to the design of the next phase of trials, Moore concludes.

Dr. Moore on Research Evaluating Repeat Exposure to PARP Inhibition in Ovarian Cancer

Kathleen Moore, MD, director, Oklahoma TSET Phase I Program, and associate professor, Section of Gynecologic Oncology, Stephenson Cancer Center, poses unanswered questions pertaining to the use and reuse of PARP inhibitors in ovarian cancer treatment.

One pressing question in the field has to do with what should be done after a patient progresses on a PARP inhibitor, says Moore. More insight is needed to understand whether that progression is due to developed resistance. If this is the case, Moore asks, “Should these patients not be given PARP inhibitors in the future or are there other strategies that can be used to overcome that resistance?”

Although PARP inhibitors show promise in extending progression-free survival in this space, they may not be appropriate for every woman with ovarian cancer, she adds. Some patients with 

 mutations or other clinical biomarkers may not derive benefit from this approach. As such, another unanswered question is whether tests can be done, or biomarkers can be identified, that could help inform appropriate selection for and sequencing of these agents.

In the United States, more women are living with ovarian cancer than ever before; this because sequenced therapies are allowing for patients to live longer, explains Moore. Early use of these therapies, as well as the development of clinical trials, could be key to combatting recurrent disease, she concludes.

Dr. Moore on Unanswered Questions With PARP Inhibitors in Ovarian Cancer 

Kathleen N. Moore, MD, assistant professor, The Stephenson Cancer Center, The University of Oklahoma, discusses the results of the NOVA trial in ovarian cancer.

mutated group, there was a statistically significant positive hazard ratio in favor of niraparib (Zejula), says Moore.

The exploratory endpoints of this trial were to further characterize the germline

-mutated group. A small group of patients with somatic BRCA mutations was identified and they seemed to get the same benefit from niraparib as the 

Dr. Moore on the Results of the NOVA Trial in Ovarian Cancer

Kathleen N. Moore, MD, assistant professor, The Stephenson Cancer Center, The University of Oklahoma, discusses the international, randomized phase III NOVA trial for recurrent platinum-sensitive ovarian cancer.

The NOVA trial aimed to determine whether the PARP inhibitor niraparib improves progression-free survival, with other endpoints being overall survival, time to first subsequent therapy, chemotherapy-free interval, and other quality-of-life measures.

This study allowed any patient with high-grade serous ovarian cancer to be split into 2 groups for independent studies.

Kathleen Moore, MD

Articles

Dr. Moore on Treatment for Patients With Ovarian Cancer Who Develop Resistance to PARP Inhibitors

Dr. Moore on Research Evaluating Repeat Exposure to PARP Inhibition in Ovarian Cancer

Dr. Moore on Unanswered Questions With PARP Inhibitors in Ovarian Cancer

Dr. Moore on the Results of the NOVA Trial in Ovarian Cancer

Dr. Moore on the NOVA Trial for Ovarian Cancer