Although there have been numerous studies evaluating the role of different therapy schedules, cytotoxic agents, and routes of administration in ovarian cancer, the backbone of therapy remains a combination of a platinum and a taxane.
Susana M. Campos, MD
Ovarian cancer is the fifth overall cause of cancer death in women, and it represents 5% of all cancers in women. Most women with ovarian cancer present with stage III or IV disease, which contributes to the high mortality rate. Although there have been numerous studies evaluating the role of different therapy schedules, cytotoxic agents, and routes of administration, the backbone of therapy remains a combination of a platinum and a taxane.
GOG-02181 and ICON72 evaluated the role of bevacizumab (Avastin) in the management of patients with newly diagnosed ovarian cancer. In GOG-0218, bevacizumab administered concurrently with chemotherapy and as maintenance treatment showed a statistically significant improvement in progression-free survival (PFS) compared with placebo (14.1 vs 10.3 months; HR, 0.717; P <.001). In ICON7, bevacizumab administered concurrently with chemotherapy and as maintenance treatment showed a statistically significant improvement in PFS compared with chemotherapy alone (19.9 vs 17.3 months; HR, 0.81; P = .004). The improvement was more pronounced for patients at high risk of progression (stage IV or FIGO [Fédération Internationale de Gynécologie et d’Obstétrique] stage III and greater than 1 cm of residual disease).
Despite these encouraging results, the addition of bevacizumab in the overall population did not result in improvement in overall survival (OS). Therefore, innovative combinations in the up-front setting of patients with ovarian cancer remain a high priority.Recently, treatment in the landscape of ovarian cancer has changed. Notably, PARP inhibitors have been approved for the treatment of recurrent ovarian cancer. In 2014, olaparib (Lynparza) was approved for patients who carried a deleterious BRCA germline mutation and had received 3 or more prior lines of chemotherapy.3 Rucaparib (Rubraca)4 was approved as single-agent maintenance therapy for patients with germline or somatic BRCA mutations.
Recently, results from 4 pivotal trials, NOVA (niraparib; Zejula),5 SOLO-2 (olaparib),6 Study 19 (olaparib),7 and ARIEL III (rucaparib),8 demonstrated a PFS benefit in patients with platinum-sensitive recurrent disease who responded to therapy regardless of mutational status. In addition to rucaparib, niraparib and olaparib are approved as maintenance therapy.
In December 2018, the FDA approved olaparib for the frontline maintenance treatment of patients with germline or somatic BRCA mutations who are in complete or partial response to platinum-based chemotherapy.9
The approval was based on findings from the international, randomized, double-blind, phase III trial that evaluated the efficacy of maintenance olaparib in patients with newly diagnosed high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with BRCA1/2 mutations who had a complete or partial response after platinum-based chemotherapy. The primary endpoint was PFS.10 After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo. The HR for disease progression or death was 0.30 (95% CI, 0.23-0.41; P <.001).9,10
Pending trials for newly diagnosed ovarian cancer that employ a PARP inhibitor include PRIMA, GOG 3005, and PAOLA-1 (Table 1).In the past several years, there has been tremendous benefit from the clinical implementation of checkpoint inhibitors, which have been approved for treatment of melanoma, Hodgkin lymphoma, and bladder, kidney, and lung cancers. However, the role of checkpoint inhibitors in ovarian cancer is undefined. Several questions remain: What effect can the immune system have on ovarian cancer? What factors contribute to ovarian cancer immunogenicity? What role does PD-L1 play in ovarian cancer?
Ovarian cancer carries a marginal level of mutational load.11 Preliminary efficacy with checkpoint inhibitors was tested in a population with recurrent unselected heavily pretreated ovarian cancer and produced an overall response rate (ORR) of 5.9% to 15%.12,13 Nivolumab (Opdivo) has demonstrated a response rate of 15% in PD-L1—positive platinum- resistant ovarian cancer.12
Recently, Matulonis et al14 reported the results of KEYNOTE-100 (NCT02674061). This study evaluated the role of pembrolizumab (Keytruda) in patients with advanced recurrent ovarian cancer. Patients received pembrolizumab at 200 mg IV every 3 weeks for 2 years or until progression, death, or unacceptable toxicity. The primary endpoint of the study was ORR by RECIST v1.1. The effect of PD-L1 expression on ORR was tested with a combined positive score assay. Overall, 378 patients were enrolled in KEYNOTE-100. The ORR was 9% (95% CI, 4%-17%) and was higher in patients with PD-L1 expression: 14% with a combined positive score ≥1 and 25% with a composite positive score of ≥10.
NRG-GY003 (NCT02498600) is a randomized, open-label, phase II trial evaluating the safety and efficacy of nivolumab with or without ipilimumab (Yervoy) as a therapy for patients with persistent or recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. This 2-arm trial has completed accrual (n = 96), with data expected in late 2020 or early 2021.
There is evidence that chemotherapeutic agents may modulate the tumor microenvironment, and there is potential that treatment could be enhanced by the addition of immune checkpoint inhibitors targeting PD-1 or PD-L1. Preclinical evidence for chemotherapy and PD-L1 inhibitors showed synergism of nab-paclitaxel (Abraxane) plus PD-L1 inhibition in MC38 mouse tumor models.15 Treatment with platinum agents or taxanes increased the percentage of CD8-positive tumor-infiltrating lymphocytes in immunocompetent mouse models.
Several trials are combining chemotherapy with checkpoint blockade. The results of 2 studies testing the activity of avelumab (Bavencio) in combination regimens have been reported. The JAVELIN OVARIAN 100 trial (NCT02718417) was terminated in December after a planned interim analysis showed that the experimental combination would not result in improved PFS, according to Merck KGaA and Pfizer, the companies developing the therapy.16
This JAVELIN OVARIAN 100 trial was a randomized phase III study in previously untreated patients with stage III to IV ovarian, fallopian tube, or peritoneal cancer. Patients were randomized 1:1 to 1 of 3 arms. Arm 1 included cytotoxic chemotherapy with carboplatin and paclitaxel followed by observation, arm 2 included chemotherapy with carboplatin and paclitaxel followed by avelumab every 2 weeks, and arm 3 included cytotoxic chemotherapy with carboplatin and paclitaxel plus avelumab every 3 weeks followed by avelumab as maintenance therapy. The primary endpoint of the study was PFS and the secondary endpoints included maintenance PFS and OS, ORR, duration of response, and patient-reported outcomes and safety.
In November 2018, the JAVELIN Ovarian 200 (NCT02580058) failed to meet the primary endpoints of improved PFS and OS, according to Merck KGaA and Pfizer.17 The trial enrolled patients with platinum-resistant ovarian cancer to either pegylated liposomal doxorubicin (PLD) plus avelumab or PLD alone.
Given the known role of PARP inhibitors in the management of ovarian cancer, investigators also are exploring whether PARP inhibitors can strengthen immune system response. PARP inhibitors can increase lymphocyte infiltration. The rationale behind this finding is that PARP inhibitors can lead to accumulation of DNA damage and cytoplasmic DNA, which stimulates the interferon gene-dependent immune response.18 Growing evidence supports the preclinical rationale for combining immune checkpoint inhibitors with DNA-damaging agents.
Recently, 2 trials highlighted the efficacy of combination treatment with a PARP inhibitor plus an immune checkpoint inhibitor in patients with ovarian cancer. The MEDIOLA trial19 treated 30 patients with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer with a combination of olaparib and the immune checkpoint inhibitor durvalumab (Imfinzi). Drew et al reported an ORR of 72% and a disease control rate of 81%. TOPACIO20 presented by Konstantinopoulos et al enrolled 62 patients with recurrent ovarian cancer treated with niraparib (200 mg oral daily) and pembrolizumab (200 mg IV on a 21-day cycle). The ORR was 25% and the disease control rate was 67%.
Numerous trials are exploring the role of combinatorial therapy with PARP inhibitors and checkpoint inhibitors in patients with newly diagnosed ovarian cancer (Table 2). In conclusion, the treatment options for patients with ovarian cancer have made a tremendous leap forward. Encouragement in clinical trials will pave the path for continued success.