PARP inhibitors: New standard in first-line therapy of ovarian cancer?

Three new studies with the PARP inhibitors niraparib, olaparib and veliparib showed a significant reduction in the risk of progression in first-line therapy of women with ovarian cancer.

Three new studies provide clear insights

Three new studies with the PARP inhibitors niraparib, olaparib and veliparib showed a significant reduction in the risk of progression in first-line therapy of women with ovarian cancer.

The results of the PRIMA, PAOLA and VELIA studies were presented at the Presidential Symposium of the European Society for Medical Oncology 2019 in Barcelona. Based on these data, PARP inhibitors are expected to become increasingly established in first-line therapy of ovarian cancer.

PRIMA study with niraparib monotherapy

For the first time, the PRIMA study presented by Antonio González Martín, Head of Medical Oncology at the University Hospital of Madrid (in Spanish: Hospital Universitario Ramón y Cajal), investigated the efficacy and tolerability of the PARP inhibitor niraparib in monotherapy in women with newly diagnosed ovarian cancer1. The GSK-funded study included 733 women with and without homologous recombination deficiency (HRD) who responded fully or partially to platinum-based chemotherapy. They were randomly treated 2:1 with niraparib or placebo for 36 months. In this overall group, 50.9% (n = 373) had an HRD mutation.

The primary endpoint, progression-free survival (PFS), was significantly prolonged from 10.4 to 21.9 months in women with HRD mutation from niraparib. This meant a 57% reduction in the risk of progression (hazard ratio 0.43, p < 0.001). In the overall group, niraparib extended PFS from 8.2 months to 13.8 months (HR 0.62, p < .001). In the 24-month interim analysis, the overall survival rate was 84% for niraparib and 77% for placebo (HR 0.70). The most common adverse effects of grade 3 or higher were anemia and neutropenia. "Niraparib monotherapy after platinum-containing chemotherapy should be considered as the new standard of care," concluded González-Martin, who had published the results in parallel in the New England Journal of Medicine (NEJM)2.

PAOLA-1 study: Olaparib plus bevacizumab as maintenance therapy

In the PAOLA-1 study, a different therapeutic approach was chosen. As Isabelle L. Ray-Coquard, Centre Leon Bérard, Université Claude Bernard, Lyon, reported, 806 women with newly diagnosed ovarian cancer were treated with platinum-based chemotherapy plus bevacizumab in the study and subsequently received maintenance therapy with bevacizumab alone for 15 months (n = 269) or with bevacizumab plus 24 months of olaparib (n = 537). Median PFS was extended from 16.6 months to 22.1 months with the addition of olaparib (HR 0.59p < 0.0001). The effect was more pronounced in women with BRCA (Breast Cancer Gene) and HRD mutations; in both subgroups, additional olaparib extended median PFS to 37.2 months. However, the rate of treatment discontinuations due to side effects was relatively high in the olaparib/bevacizumab group (20%) and 6% in the placebo/bevacizumab group (6%).

VELIA study: Veliparib plus chemotherapy

The VELIA study presented by Robert L. Coleman, MD from the Anderson Cancer Institute, Houston, Texas, was also published in parallel in the NEJM4, 5. This Abbvie-funded study included 1,140 untreated patients with advanced ovarian cancer. They were randomized into 3 groups and received:

The primary endpoint was the PFS, and the data presented was consistent between the Veliparib group compared to the control group. The addition of the PARP inhibitor to chemotherapy with maintenance therapy showed a significant benefit. In the intention-to-treat group, median PFS increased from 17.3 months to 23.5 months (HR 0.68, p < 0.001). In patients with BRCA mutation, PFS was 34.7 months with continuous Veliparib administration compared to 22 months in the control group (HR 0.44, p < 0.001). In HRD, PFS was 31.9 and 20.5 months, respectively (HR 0.57, p < 0.001). Additional administration of Veliparib increased the incidence of anemia, thrombocytopenia, nausea, and fatigue.

A new standard in first-line therapy

"We are witnessing a shift in first-line therapy for advanced ovarian cancer," concluded Ana Oaknin, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, who was the data discussant at the ESMO Congress. The studies showed a robust reduction in progression risk, which would clearly justify the use of PARP inhibitors in first-line therapy. First-line therapy is the only opportunity to cure a patient because the main objective in ovarian cancer is to prevent recurrence after first-line therapy, otherwise, the chances of cure are very poor. "After decades of investigating different chemotherapies, we have now achieved a significant progression-free survival extension for the first time and hopefully we can also improve the long-term benefit," said Oaknin.

Mansoor Raza Mirza, Rigshospitalet, Copenhagen, and discussant of the VELIA study also stated: "Now is the time to offer all patients a PARP inhibitor.” He pointed out that all 3 trials had included all patients and showed that women without BRCA mutations could also benefit.

Sources:
1. González-Martín A. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study), ESMO 2019 Annual Meeting, 27. September until 1. October 2019, Barcelona, LBA1.
2. González-Martín A. et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. NEJM 2019, published online on 28. September 2019.
3. Ray-Coquard I. Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy plus bevacizumab. ESMO 2019 Annual Meeting, 27. September until 1. October 2019, Barcelona, LBA2.
4. Coleman RL. VELIA/GOG-3005: Integration of veliparib with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin. ESMO 2019 Annual Meeting, 27. September until 1. October 2019, Barcelona, LBA3.
5. Coleman RL et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. NEJM 2019, published online on 28. September 2019

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