The ongoing phase III JAVELIN Ovarian PARP 100 study, which was evaluating the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance avelumab in combination with talazoparib in patients with locally advanced or metastatic ovarian cancer, has been discontinued.
The ongoing phase III JAVELIN Ovarian PARP 100 study (NCT03642132), which was evaluating the efficacy and safety of avelumab (Bavencio) in combination with chemotherapy followed by maintenance avelumab in combination with talazoparib (Talzenna) in patients with locally advanced or metastatic ovarian cancer, has been discontinued, according to Merck KGaA and Pfizer, the companies that collaborated on the trial.1
The discontinuation stems from factors that include previously announced interim data of the JAVELIN Ovarian 100 trial, which ended in December 2018 after an independent panel determined the study would not meet its primary endpoint of progression-free survival (PFS). Therefore, those findings did not support continuation of JAVELIN Ovarian PARP 100 in an unselected patient population, the companies stated in a press release.
Although safety was not a deciding factor, additional reasons for terminating the trial included recently approved treatment options for patients with ovarian cancer, including the December 2018 FDA approval of olaparib (Lynparza) as a maintenance treatment for patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy.
The companies, which emphasized a need to better understand the role of immunotherapy in ovarian cancer, have notified health authorities as well as study investigators of the decision to end the study. This discontinuation does not affect current indications of avelumab nor the remainder of the ongoing JAVELIN clinical development program.
In the international, open-label, multicenter, JAVELIN Ovarian PARP 100 trial, investigators randomized treatment-naïve patients with locally advanced or metastatic ovarian cancer to receive avelumab in combination with chemotherapy followed by maintenance avelumab in combination with talazoparib versus an active comparator. The estimated enrollment was 720 patients.
Patients who could enroll on the trial had either stage III or stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer and must have been eligible to receive bevacizumab (Avastin) in combination with platinum-based chemotherapy.
Those who had nonepithelial tumors or ovarian tumors with low malignant potential, or mucinous tumors; planned intraperitoneal cytotoxic chemotherapy; prior exposure to immunotherapy, a PARP inhibitor, or a VEGF inhibitor; major surgery within 4 weeks of randomization and/or incomplete recovery from surgery; prior radiotherapy to any portion of the abdominal cavity or pelvis; prior targeted therapy or organ transplantation; diagnosis of myelodysplastic syndrome; or known symptomatic brain metastases requiring steroids were excluded.
The primary endpoint was PFS as determined by blinded independent central review assessment per RECIST v1.1 criteria; secondary endpoints included overall survival (OS), Euro Quality of Life, and PFS2.
JAVELIN Ovarian 100 (NCT02718417) was exploring frontline avelumab in 998 treatment-naïve patients with locally advanced or metastatic (stage III/IV) epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Patients were randomized to carboplatin/paclitaxel, carboplatin/paclitaxel with maintenance avelumab, or avelumab plus carboplatin/paclitaxel followed by maintenance avelumab.
At a planned interim analysis, an independent data monitoring panel determined that neither of the 2 avelumab arms would demonstrate a PFS benefit over the control arm of chemotherapy alone.2 Moreover, there were no new safety signals. The companies had stated in a prior news release that they plan to share specific data from this study at a later date.
Prior to the JAVELIN Ovarian 100 announcement, the companies also reported that results of the multicenter, phase III JAVELIN Ovarian 200 trial (NCT02580058) demonstrated that single-agent avelumab or the PD-L1 inhibitor plus pegylated liposomal doxorubicin (PLD) did not lead to a statistically significant improvement in OS or PFS compared with PLD alone in patients with platinum-resistant/refractory ovarian cancer.3
In the study, 556 patients with platinum-resistant/refractory ovarian cancer were randomized to receive either avelumab intravenously (IV) at 10 mg/kg every 2 weeks in 4-week cycles, avelumab IV at 10 mg/kg every 2 weeks in 4-week cycles plus PLD at 40 mg/m2 IV every 4 weeks in 4-week cycles, or PLD at 40 mg/m2 IV every 4 weeks in 4-week cycles.
Patients had histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, platinum-resistant/-refractory disease, previously received up to 3 lines of systemic therapy, and measurable disease. The primary endpoints were superior OS or PFS for one or both avelumab arms versus PLD, and objective response rate (ORR) was a secondary endpoint.
Findings showed that avelumab plus PLD led to an HR for PFS of 0.78, which did not meet the prespecified criteria for superiority (repeated confidence interval [RCI], 0.587-1.244; one-sided P value = .0301). Additionally, the OS endpoint with the avelumab combination was also not met (HR, 0.89; RCI, 0.744-1.241; one-sided P value = .2082).
Single-agent avelumab missed the PFS endpoint (HR, 1.68; RCI, 1.320-2.601; one-sided P value >.99) and OS endpoint (HR, 1.14; RCI, 0.948-1.580; one-sided P value = .8253). The ORR was 13.3% (95% CI, 8.8%-19.0%) for avelumab combined with PLD, 3.7% (95% CI, 1.5%-7.5%) for single-agent avelumab, and 4.2% (95% CI, 1.8%-8.1%) for PLD alone. There were no new safety signals reported with either avelumab monotherapy or with the combination.