PARP Inhibitors Are Changing Paradigm in Recurrent Ovarian Cancer

Bradley J. Monk, MD

Platinum and taxane chemotherapies remain standard first-line treatments for epithelial ovarian cancer. The treatment of recurrent ovarian cancer has historically been based on how a patient responded to the first-line regimen. Patients whose cancer recurred 6 months or more after the last platinum infusion are categorized as platinum-sensitive, whereas patients whose cancer recurred within 6 months of the last infusion are classified as platinum-resistant. Greater understanding of ovarian cancer biology and the emergence of new targeted therapies is diminishing the importance of platinum response in determining how to treat recurrent disease.

The Importance of Ovarian Cancer Biology

During an OncLive Peer Exchange^® titled “Expert Views on Therapy for Ovarian, Fallopian Tube, and Peritoneal Cancers,” a panel of gynecologic oncology specialists discussed novel agents for the second, third, fourth, and even fifth lines of therapy and the growing importance of molecular signature, histology, and time to recurrence in treatment decisions. As panel moderator Bradley J. Monk, MD, summarized, “We have had 3 new FDA approvals for targeted therapies in the last 2 years, and I anticipate within the next year, we’ll have 3 more. Our armamentarium is growing, and our paradigms are changing.”Ovarian cancer, like cancers that affect other organs, comprises many subtypes. Approximately 90% are epithelial, 80% of which are subcategorized as serous carcinomas.¹ Serous carcinomas are further divided into high grade and low grade, with high grade accounting for 90% of serous tumors.¹ “High-grade serous patients tend to have the worst prognosis compared to those with low-grade serous cancers,” said Angeles Alvarez Secord, MD. She said high-grade serous tumors are further classified according to whether they harbor a homologous recombination deficiency (HRD), such as a germline or somatic BRCA mutation.

The BRCA gene helps repair DNA and suppresses tumor growth, and current guidelines recommend all women with epithelial ovarian cancer have a blood test for a germline BRCA alteration. Monk said it surprises him when he meets a new patient who has had epithelial ovarian cancer for a long time but never had a BRCA test. Thomas Herzog, MD, said some experts recommend clinicians also test the tumor for a somatic BRCA mutation, which a blood test would not detect. Kathleen N. Moore, MD, reminded everyone that HRD testing is another option. She said although an HRD test does not identify specific somatic mutations, it does indicate whether a patient has an important somatic mutation in the DNA repair pathway.

PARP Inhibitors

Robert L. Coleman, MD, said it is important to know whether the “machinery is messed up,” because the cancer cell may have a vulnerability able to be exploited with drugs that induce DNA damage. Secord called the process synthetic lethality. “If somebody has that BRCA mutation—whether it’s germline or somatic—or they have another defect that’s causing loss of homologous recombination, then the cells can’t repair themselves once they’re subjected to a DNA-damaging event,” Secord said. Coleman said synthetic lethality explains why patients with high-grade serous ovarian cancers who have a BRCA mutation have better outcomes than patients without a BRCA mutation. The same gene that predisposes their cells to malignant transformation makes those malignant cells vulnerable to DNA-damaging drugs.The poly(ADP-ribose) polymerase (PARP) protein plays a significant role in repairing DNA damage. Monk described how the class of drugs known as PARP inhibitors are designed to block PARP’s enzymatic activity, thereby disrupting DNA repair and causing an accumulation of single-stranded breaks.“If you can’t repair single-stranded breaks, you get a double-stranded break. And if you have a BRCA or BRCA-like mutation, you can’t repair the double- stranded break [and] the cell dies,” he said.

The FDA has approved 2 PARP inhibitors for women with ovarian cancer. In 2014, olaparib (Lynparza) received accelerated approval for women with advanced ovarian cancer who have a germline BRCA mutation and used at least 3 prior lines of chemotherapy. Approval was based on data from a phase II trial that included 193 heavily pretreated patients with ovarian cancer and a germline BRCA mutation.² The overall response rate (ORR) in this cohort was 31%, and median progression-free survival (PFS) was 7 months.² Herzog said the most common adverse events (AEs) in the phase II trial were fatigue and anemia. Some patients also experienced gastrointestinal issues, which Herzog said may have been because the formulation of olaparib used in the trial required patients to take 16 capsules per day.

Moore said the phase III SOLO-2 trial, which is meant to be a confirmatory study, uses a new tablet formulation of olaparib. Patients will require fewer tablets than capsules, and Monk speculated the new formula might reduce gastrointestinal toxicity. SOLO-2 recruited women with platinum-sensitive, BRCA-mutated recurrent ovarian cancer and randomly assigned them to olaparib tablets or placebo. “That study has been reported to be positive in a press release but without any accompanying hazard ratio as of yet, so we’re awaiting data,” Moore said. SOLO-3 is another ongoing trial, which is comparing olaparib with physician’s choice of standard chemotherapy in recurrent ovarian cancer.

During the December 9, 2016, OncLive Peer Exchange® panel, Monk accurately predicted that the FDA would soon approve a new PARP inhibitor, rucaparib (Rubraca). On December 19, the FDA granted accelerated approval to rucaparib and to a companion diagnostic test, the FoundationFocus CDxBRCA, which screens ovarian tumor tissue for BRCA gene mutations.³ Rucaparib is indicated for women with advanced ovarian cancer who have received 2 or more lines of chemotherapy and whose tumor harbors a germline or somatic BRCA mutation.

Approval was based on findings from 2 single-arm clinical trials (ARIEL2 and Study 10), which included women with BRCA-mutated advanced ovarian cancer. “They particularly were interested in looking at those patients who had a germline or a somatic BRCA mutation and had received greater than 2 lines of prior chemotherapy,” Moore said. At the 2016 European Society for Medical Oncology Congress, Rebecca Kristeleit, PhD, presented a pooled efficacy analysis for 106 women in the studies, which showed an investigator ORR of 53.8% and a median PFS of 9.2 months.⁴ Moore praised the remarkable outcomes and the safety profile; she said most AEs observed in the studies were common class effects of PARP inhibitors.

Coleman and his colleagues recently published additional findings from ARIEL2, which showed rucaparib was more effective in patients with a BRCA mutation and in women without a BRCA mutation who had a high degree of genomic loss of heterozygosity (LOH), or what Coleman called“genomic scarring.”⁵ Coleman said, “Rather than going through and trying to pick off which genes are actually the vulnerable ones...it was just easier to look across all of the genes.”

Table. Progression-Free Survival for Niraparib Versus Placebo in the NOVA Ovarian Cancer Trial⁶

Niraparib is another PARP inhibitor the panel predicted was likely to earn FDA approval. Niraparib was evaluated in the phase III NOVA trial (n = 553) as maintenance therapy for women with platinum-sensitive, recurrent ovarian cancer.6 The authors stratified the women into 3 cohorts: those with a germline BRCA mutation, those without one, and those without one who were HRD positive. “The maintenance niraparib approach resulted in improved PFS in all 3 groups,” Secord said (Table). She added that when she first learned of the results, she assumed patients with a somatic tumor mutation accounted for the positive results in the niraparib cohort of women with no germ- line mutation. She was pleasantly surprised to find niraparib also benefited women who carried neither a germline nor a somatic BRCA mutation, but who were HRD positive.

“I’m still confused about this maintenance idea,” Monk said. “In the NOVA trial, maintenance is in the title, but half the patients still have cancer. How can I call that maintenance if they had partial responses until their last treatment?” The experts agreed the terminology was imperfect, and Herzog suggested the NOVA trial was more like a switch study.

Which PARP Is Best?

Veliparib is a fourth PARP inhibitor, which is being evaluated in an ongoing phase 3 trial as an addition to standard frontline chemotherapy for ovarian cancer and as maintenance therapy after chemotherapy. “Myelosuppression becomes a very real issue with DNA-damaging chemotherapy, but veliparib is probably less potent [than the other PARP inhibitors] on that specific angle,” Coleman said.No trials have compared the PARP inhibitors head- to-head for ovarian cancer, and the panel agreed on the need for caution when making cross-trial comparisons. “You need to be aware of what the methodology was—it’s very important,” Herzog said. He suggested clinicians look at the toxicities observed with each PARP inhibitor and the labels once they are all approved.

“There are some differences between these drugs and how they bind to the different PARP receptors,” Secord said. She pointed out that niraparib is associated with a higher risk of thrombocytopenia than other PARP inhibitors. Herzog noted that the PARP inhibitors also have differences in bioavailability.

Moore said it was too early to know whether one PARP inhibitor was better than another. “Certainly they have differences in the Petri dish in terms of potency, but even the 3 we’re talking about are all pretty potent PARP inhibitors, and they all work in the studies that they have been tested in,” she said.

Ongoing trials of the various PARP inhibitors should provide more data to guide clinicians’ choices once they are all available for use in practice. Some studies are assessing outcomes by HRD score, others are assessing PARP inhibitors as frontline therapy or in combination with other classes of agents, such as VEGF inhibitors. Herzog predicted future trials would likely combine them with immune checkpoint inhibitors and other immunotherapies. The panelists expressed excitement about the many new options available for their patients. “We’ve had a real change—a paradigm shift,” Herzog said.

The group agreed that despite the advances, many challenges remain, such as drug resistance. Herzog said he expects the recent evolution in clinical trial design will lead to data-driven answers to critical questions, such as how to sequence PARP inhibitors with other agents or which combinations work best for which patients. “We have a light at the end of the tunnel,” Coleman concluded.

References

1. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi24-vi32.
2. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250. doi:10.1200/JCO.2014.56.2728.
3. US Food and Drug Administration. FDA grants accelerated approval to new treatment for advanced ovarian cancer [press release]. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm533873.htm. Published December 19, 2016. Accessed January 16, 2017.
4. Kristeleit RS, Shapira-Frommer R, Oaknin A, et al. Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high-grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut); analysis of pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2). Ann Oncol. 2016;17(suppl 6):vi2i6-vi312.
5. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87. doi:10.1016/S1470-2045(16)30559-9.
6. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi:10.1056/NEJMoa1611310.