Women with ovarian cancer who have undergone four or more rounds of chemotherapy typically haven’t had much hope that another treatment option will lengthen their lives in a meaningful way.
However, a new research study shows tremendous promise for a drug called niraparib to extend life when all options have been exhausted.
Gynecologic oncologist Kathleen Moore, M.D., associate director of clinical research at the Stephenson Cancer Center at OU Medicine, is the lead author for the study, which was published in The Lancet Oncology, the world’s leading cancer journal.
The study reveals especially good news for patients with ovarian cancer who do not have a mutation of their BRCA gene, as well as those who have received multiple chemotherapy treatments.
Because the study showed a longer survival time for those patients, it lends support for an expansion of the use of niraparib, a PARP inhibitor that targets cancer cells without affecting normal cells.
“This is another piece of the puzzle that helps our patients live longer,” Moore said.
“There haven’t been a lot of studies done on patients without BRCA mutations who have received four, five, six or more lines of chemotherapy.
That’s who this trial sought to study. Until we can cure patients, we are doing our best to find treatments that buy them meaningful periods of time, until we can provide them with the next effective line of therapy.”
Because women with BRCA-associated cancers respond best to PARP inhibitors, they have been the most heavily studied group and led to the first indications for using the drugs in treating ovarian cancer. However, only about 25 percent of women with ovarian cancer have a BRCA mutation either in their tumor or blood, and there is a high unmet need for effective therapies for the 75 percent of women who do not have BRCA mutations, Moore said.
Ironically, having a BRCA mutation means that the patient’s cancer will respond better to chemotherapy and to a PARP inhibitor like niraparib.
Women with BRCA mutations have something called homologous recombination deficiency – which means that when their cancer cells make mistakes in the process of dividing, they have trouble repairing those mistakes. PARP inhibitors like niraparib make repairing those mistakes even harder, which equates to treatment being able to kill cancer cells more efficiently.
However, women with BRCA mutations aren’t the only cancer patients who have homologous recombination deficiency. Up to 25 percent of women without a BRCA mutation can also develop the condition, meaning they, too, can benefit from taking a PARP inhibitor.
The study further categorized patients into those who were resistant to platinum-based chemotherapy and those who showed some response to it.
Among women who responded to their last chemotherapy treatment, 27 percent responded well to niraparib and averaged 9.2 months until the disease grew or spread.
Participants in the study had an overall survival time of more than 20 months, which is quite remarkable in this late line of therapy, Moore said.
“We don’t normally see response rates of more than 10 percent in women who have had four, five and six chemotherapy treatments,” she said.
“So a 27 percent response, especially given that these were not all women with BRCA mutations, was a nice signal that these patients can still benefit from PARP inhibitor use.”
Even among women whose cancers were resistant to their last chemotherapy treatment, niraparib still extended their lives. Thirty-three percent of women in that category benefited from the drug for at least four months.
“Those additional months are important,” Moore said.
“They are never enough, but several months of disease stabilization is better than none.
They can get people to Christmas or to see a new grandchild or to another milestone. Then, if they are stabilized and feeling better, they might be able to take another drug or go on a clinical trial.”
Research studies also are important for expanding the types of patients who can receive a drug like niraparib,
Moore said. Per FDA regulations, the only way that women without a BRCA mutation can currently receive niraparib is to respond favorably to platinum-based chemotherapy, then go on the drug as maintenance.
“We think this data supports the expansion of niraparib to be more inclusive of patients. PARP inhibitors work best in women with BRCA mutations, but they can still work well in women without the mutation. Niraparib really makes sense for a much broader population,” said Moore, who holds the Virginia Kerley Cade Endowed Chair in Cancer Developmental Therapeutics, funded by the Presbyterian Health Foundation.
Ovarian cancer is the eighth leading cause of deaths due to cancer worldwide, with a 5-year survival rate ranging from 30% to 50%.
Although most patients initially have platinum-sensitive ovarian carcinoma, their disease eventually becomes resistant or refractory to platinum-based chemotherapy.1,2
Some patients are unable to receive platinum-based chemotherapy owing to cumulative toxic effects or allergic reactions and receive non–platinum-based agents such as weekly paclitaxel, pegylated liposomal doxorubicin hydrochloride, or topotecan hydrochloride alone or in combination with bevacizumab.3,4
Owing to the risk of vascular toxic effects and gastrointestinal tract perforation, bevacizumab is contraindicated in approximately one-third of patients5; non–platinum-based monotherapy in these patients results in low response rates (10%-15%) and short durations of response (3-4 months).6
The treatment armamentarium for ovarian carcinoma has recently been expanded to include poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors. PARPs are enzymes that detect DNA damage and promote repair by several mechanisms.
Inhibition of PARP1/2 in cells that are already deficient in DNA repair mechanisms, such as those with BRCA(OMIM 113705 and 600185) mutations or homologous recombination deficiency (HRD), causes increased genomic instability and ultimately cell death.
This synergism between cellular defect and drug-induced effect is termed synthetic lethality. Patients with BRCA wild-type (BRCAwt) tumors also benefit from PARP inhibition induced by niraparib; this effect is thought to be driven by high tumor accumulation of niraparib.7
Niraparib is approved in the United States and European Union for the maintenance treatment of recurrent ovarian carcinoma for patients with a complete or partial response to platinum-based chemotherapy.8,9
This approval was based on results from the European Network of Gynaecological Oncological Trial Groups (ENGOT)-OV16/NOVA trial,10 which demonstrated that treatment with niraparib significantly improved progression-free survival along a graduated continuum.
The strongest effect was observed in patients with germline BRCA-mutated (gBRCAmut) tumors (hazard ratio [HR], 0.27), followed by patients with HRD-positive/gBRCAwt tumors (HR, 0.38) and those with HRD-negative tumors (HR, 0.58).10
Programmed cell death receptor 1 (PD-1) is a checkpoint receptor that is expressed on activated T cells.
Its associated ligands, programmed death-ligands 1 and 2 (PD-L1 and PD-L2), are frequently expressed on neoplastic cells. Ligand receptor binding results in downregulation of the immune response.
Antibodies targeting PD-1 have emerged as promising therapies for several types of cancers by promoting T cell–mediated killing.11 Preclinical models, including those for ovarian carcinoma, have demonstrated a synergistic antitumor effect with niraparib and anti–PD-1 drugs regardless of BRCA mutation status or PD-L1 expression.12
The immunomodulatory function of niraparib has been proposed as a potential mechanism for this synergy based on the observation that niraparib treatment significantly increased the activities of the stimulator of interferon gene and interferon pathways and enhanced intratumoral immune cell infiltration and upregulation of granzyme B–positive T cells.12,13
Other mechanisms, such as PARP inhibitor–mediated upregulation of PD-L1 expression, may also play a role in the activity of this combination.14,15 The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial evaluated the hypothesis that niraparib combined with an anti–PD-1 antibody (pembrolizumab) would be safe and effective in populations with difficult-to-treat ovarian carcinoma.
Importance Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited.
Objective To evaluate the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma.
Design, Setting, and Participants The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCAmutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019.
Interventions The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.
Main Outcomes and Measures The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis.
Results Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment.
Conclusions and Relevance Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.
Trial Registration ClinicalTrials.gov identifier: NCT02657889
More information: Kathleen N Moore et al, Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial, The Lancet Oncology (2019). DOI: 10.1016/S1470-2045(19)30029-4
Journal information: Lancet Oncology
Provided by University of Oklahoma
