- TOPACIO data for ZEJULA® (niraparib) in combination with an anti-PD-1 mAb highlight promising activity in platinum-resistant/refractory ovarian cancer and triple-negative breast cancer beyond patients with BRCA mutations and support initiation of registration trials
- QUADRA results demonstrate durable responses beyond patients with BRCA mutations in late-line ovarian cancer treatment setting and support label expansion
- Investor webcast to highlight ZEJULA’s differentiation in difficult-to-treat ovarian cancer settings and potential in triple-negative breast cancer
“The promising data presented at this year’s
TOPACIO Data Demonstrate Encouraging Activity of Niraparib in Combination with anti-PD-1 in Platinum-Resistant/Refractory Ovarian Cancer
Prior clinical studies have shown that monotherapy with PARP inhibitors or anti-PD-1 antibodies has limited efficacy in the treatment of patients with platinum-resistant/refractory ovarian cancer or triple-negative breast cancer beyond those patients with BRCA mutant tumors, and these patients generally face a poor prognosis. TOPACIO is a Phase 1/2 clinical trial designed to evaluate the safety and efficacy of niraparib plus KEYTRUDA® (pembrolizumab) in patients with recurrent, platinum-resistant/refractory ovarian cancer or triple-negative breast cancer (TNBC). Following dose finding in Phase 1, niraparib was administered orally, once-daily, at a dose of 200 milligrams in combination with 200 milligrams of pembrolizumab administered intravenously on day one of each 21-day treatment cycle in two patient cohorts: platinum-resistant or refractory ovarian cancer and TNBC. Endpoints included objective response rate (ORR), duration of response (DOR) and disease control rate (DCR; CR+PR+SD).
At the time of data cutoff, of the 62 patients enrolled with ovarian cancer, 60 were evaluable for an initial response assessment. The population had been treated with a median of 2 (range of 1 to 5) prior lines of therapy; 50% had platinum-resistant ovarian cancer, 29% were platinum-refractory, 63% had received prior bevacizumab, and 21% were platinum ineligible. Data indicate an ORR (CR and PR) of 25% and a DCR of 67% in the evaluable population; ORR in the BRCAmut cohort was 25% with a DCR of 63%; ORR in the BRCAwt cohort was 24% with a DCR of 65%. Response rates were not dependent on biomarker status or platinum status. ORR was 23% (7/30) in platinum-resistant ovarian cancer patients, 24% (4/17) in platinum-refractory patients and 31% (4/13) in patients who were platinum ineligible per investigator’s assessment (typically due to prior platinum hypersensitivity, toxicities or other reasons that platinum could not be tolerated). Median DOR was 9.3 months, with 9 patients remaining on treatment. The most common grade ≥ 3 adverse events (AEs) included anemia (21%) and thrombocytopenia (9%) at a 200-milligram starting dose of niraparib. Following a successful discussion with
For patients with platinum-resistant ovarian cancer, response to chemotherapy is 5-18%, including the most commonly prescribed regimen in the U.S., bevacizumab plus pegylated liposomal doxorubicin1. Platinum refractory patients typically have even lower response rates and NCCN treatment guidelines recommend clinical trials for these patients2. Historical response to PARP inhibitors is 5-10% in patients without BRCA mutations who have platinum resistant disease3 and 0-14% in those with BRCA mutations and platinum refractory disease4. Response rates of 10-15% have been reported with anti-PD-1 antibodies in this ovarian cancer population5.
TOPACIO Results in Advanced Triple-Negative Breast Cancer Show Encouraging Activity of Niraparib in Combination with anti-PD-1
At the time of data cutoff, of the 55 patients enrolled with TNBC, 46 were available for an initial response assessment, 15 of whom had BRCA mutations and 5 of whom were HRRmut. In the TNBC population evaluable for initial response assessment, ORR was 28% and DCR was 50%, while in the BRCAmut population, ORR was 60% and DCR was 80%, with mPFS of 8.3 months. In the combined BRCAmut plus HRRmut population, ORR was 55% and DCR was 80%, with mPFS of 6.4 months. Median DOR has not been reached with 62% (8/13) of responders remaining on treatment, including five patients with long-term, ongoing clinical benefit for approximately one year. The combination was well tolerated with the most commonly observed grade ≥ 3 AEs including anemia (15%) and thrombocytopenia (13%). Of note, the incidence of thrombocytopenia was substantially reduced with the 200-milligram dose of niraparib in both the ovarian cancer and TNBC cohorts in comparison to what has been observed in clinical trials with a starting dose of 300 milligrams niraparib. Following a successful discussion with
For patients with TNBC, the standard of care is chemotherapy6, which generally results in a median PFS in the range of three to five months, and median overall survival of ≤ 12 months7. PARP inhibitor monotherapy has demonstrated clinical activity in TNBC patients who are germline BRCA mutation carriers, but has not shown activity in breast cancer beyond gBRCAmut patients8. Anti-PD-1 antibody monotherapy has demonstrated modest activity in previously treated PD-1L positive TNBC, with an ORR of approximately 5-18% and median PFS of approximately two months9.
The TOPACIO trial is being conducted in collaboration with
QUADRA Results Demonstrate Durable Potential of ZEJULA in Late-Line Ovarian Cancer Setting Beyond Patients with BRCA Mutations
Previous studies have shown that meaningful activity of other PARP inhibitors in the late-line treatment of ovarian cancer is limited to populations with BRCA mutations. Efficacy of cytotoxic chemotherapy is limited in patients with heavily-pretreated ovarian cancer. QUADRA, a single arm study (n=463), was conducted to assess the activity of ZEJULA monotherapy in the fourth-line or greater treatment of patients with ovarian cancer, regardless of platinum or biomarker status. In QUADRA, less than 20% of patients had a BRCA mutation, 27% received niraparib as a sixth or later line therapy, two-thirds were platinum resistant or refractory (33% and 35%, respectively), and 48% were HRD positive. The majority of platinum sensitive patients who enrolled in QUADRA were considered platinum ineligible, and 62% had received prior bevacizumab. The median time from last chemotherapy until the first dose of niraparib was two months.
The primary efficacy population included fourth or fifth line patients who were previous PARPi naïve, platinum sensitive, and HRD positive (n= 45). The ORR in this population was 29% (95% CI 16-44, p=0.0003). Approximately one-third of patients (27%) enrolled in QUADRA were treated in the sixth or later line of therapy. For patients who were fourth or later line, HRD-positive and platinum sensitive (n=51), the ORR was 27%, the disease control rate (DCR; CR + PR + SD) was 69%, and DOR was 9.2 months. Among those treated in fourth or later line of therapy, clinical benefit (CR+PR+SD) rate for at least 16 weeks was 53% for patients with a BRCA mutation and 49% for patients who were HRD positive and platinum sensitive. Responses to niraparib were durable, with a median DOR of 9.4 months across the entire evaluable patient population. An estimated 44% of all responses lasted 12 months or more.
Median overall survival (OS) in all patients treated fourth line or later was 17.2 months. Median OS was 16.6 months in HRD-negative or unknown patients, 19.0 months in HRD-positive patients and 26.0 months in patients with BRCA mutations.
At a starting dose of 300 milligrams of ZEJULA, the most commonly observed grade 3 or higher adverse events were consistent with prior clinical experience and included anemia (26.3%) and thrombocytopenia (20.5%), which were generally managed via dose modifications.
Investor Briefing and Webcast
About the QUADRA Clinical Trial
QUADRA is an open-label, single arm trial designed to evaluate the safety and efficacy of ZEJULA in the treatment setting of ovarian cancer. Patients were enrolled and received a starting dose of 300 milligrams of niraparib once per day. The primary endpoint of this study was objective response rate (ORR) per RECIST in the fourth and fifth-line HRD positive patients who were PARP inhibitor naïve, and platinum sensitive. Other endpoints include durability of response, disease control rate, progression free survival (PFS), overall survival (OS) and safety and tolerability.
About ZEJULA® (Niraparib)
Niraparib is marketed in
ZEJULA (niraparib) Select Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in patients treated with ZEJULA in some clinical studies. Discontinue ZEJULA if MDS/AML is confirmed.
Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time.
Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for one month after receiving the final dose.
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1 Bevacizumab Prescribing Information
2 NCCN clinical practice guidelines in oncology. Ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. Version 2. 2018. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf [accessed 03.25.18]
3 Gelmon, et al. Lancet Oncol 2011; Sandhu, et al. Lancet Oncol 2013
4 Fong J Clin Oncol 2010, Domchek, et al. Gyn Oncol 2016;
5 Hamanishi, et al.
6 Bianchini G et al. Nat Rev
7 Kim SB et al. Lancet Oncol. 2017 Oct;18(10):1360-1372; O’Shaughnessy et al. J Clin Oncol. 2017;
8 Robson M et al. N Engl J Med. 2017 Aug 10;377(6):523-533.
9 Nanda R et al. J Clin Oncol. 2016 Jul 20;34(21):2460-7; Adams S et al. J Clin Oncol. 2017;35 (suppl 15):1008;
Source: TESARO, Inc.