Paradigm Shift: PARP Inhibitors Should Be Offered to All Patients with Ovarian Cancer

TOP - January 2020, Vol 13, No 1
Phoebe Starr

Barcelona, Spain—Poly (ADP-ribose) polymerase (PARP) inhibition has an established role as maintenance therapy in women with newly diagnosed high-grade advanced ovarian cancer and a BRCA mutation. At the ESMO Congress 2019, results of 3 clinical trials expand the use of PARP inhibition in ovarian cancer to all patients. The 3 studies had different enrollment criteria, used a different PARP inhibitor, and 2 of them used PARP inhibitor plus bevacizumab (Avastin); however, taken together, all 3 trials show that the PARP inhibition era is here.

Susana Banerjee, MBBS, MA, PhD, FRCP, Consultant Medical Oncologist, Royal Marsden NHS Foundation Trust, London, England, commented on all 3 trials at a press conference. “Since last year’s practice-changing SOLO1 trial was presented, olaparib [Lynparza] maintenance therapy has become standard of care for women with newly diagnosed ovarian cancer and a BRCA mutation. These 3 phase 3 trials…are incredibly important and are highly likely to shape clinical practice internationally for newly diagnosed ovarian cancer patients with and without a BRCA mutation.”

“Ongoing phase 3 first-line trials will help address whether PARP inhibitors in combination with immunotherapy can further improve outcomes in ovarian cancer. The ultimate goal is to have more long-term survivors and more women cured of this devastating disease,” Dr Banerjee said.

“The time has come to offer all patients a PARP inhibitor,” said Mansoor Raza Mirza, MD, Chief Oncologist, Department of Oncology, Copenhagen University Hospital, Denmark, who discussed the 3 studies.

Study 1: PRIMA/ENGOT-OV26/GOG-3012

A total of 733 patients who responded to 6 to 9 cycles of first-line platinum-based chemotherapy were randomized in a 2:1 ratio to niraparib (Zejula) maintenance versus placebo. The study population included patients at high risk for progressive disease. Of all randomized patients, 33 (50.9%) had homologous recombination repair deficiency (HRD); among these, 223 had BRCA-positive tumors and 150 had tumors without BRCA mutations. Of note, bevacizumab was not part of the treatment regimen.

On October 23, 2019, the FDA approved a new indication for ni­raparib for patients with advanced ovarian, fallopian tube, or peritoneal cancer associated with HRD-positive status who had received ≥3 chemotherapy regimens. HRD is defined by the presence of a BRCA mutation or genomic instability associated with disease progression ≥6 months after response to platinum-based chemotherapy.

In the overall study population, the median progression-free survival (PFS) was 13.8 months with niraparib maintenance versus 8.2 months with placebo (P <.001). In patients with HRD, the median PFS was 21.9 months with niraparib maintenance therapy versus 10.4 months with placebo (P <.001). The 24-month overall survival (OS) was 84% with niraparib versus 77% with placebo. The magnitude of the OS benefit was greater in patients with HRD, but all patients benefited from niraparib maintenance.

The most common grade ≥3 adverse events were anemia (31%), thrombocytopenia (28.7%), and neutropenia (12.8%).

“Niraparib is the first PARP inhibitor to demonstrate benefit in patients across the biomarker subgroups after front-line platinum-based chemotherapy, consistent with prior studies of niraparib in recurrent ovarian cancer,” said lead investigator Antonio González Martín, MD, PhD, Co-Director, Department of Medical Oncology, Clínica Universidad de Navarra, Madrid, Spain. “Niraparib monotherapy after first-line platinum-based chemotherapy should be considered a new standard of care,” he advised.

The results of this study were published online in the New England Journal of Medicine.1

Study 2: PAOLA-1/ENGOT-ov25

The PAOLA-1/ENGOT-ov25 study was the first phase 3 clinical trial to evaluate the safety and efficacy of the combination of the PARP inhibitor olaparib plus bevacizumab for first-line maintenance treatment for patients with ovarian cancer, with and without a BRCA mutation. A total of 806 patients who responded to platinum-based chemotherapy plus bevacizumab were randomized to a maintenance regimen with olaparib plus bevacizu­mab or to placebo.

The median PFS of olaparib plus bevacizumab maintenance therapy was 22.1 months versus 16.6 months with placebo (P <.0001) in the overall study population, irrespective of BRCA status.

As in Study 1, the magnitude of the benefit with the PARP inhibitor plus bevacizumab combination was greater in patients with BRCA mutations—the median PFS was 37.2 months versus 21.7 months, respectively.

Patients with HRD-positive ovarian cancer, regardless of BRCA mutation, also had a PFS benefit from olaparib plus bevacizumab, with a median PFS of 37.2 months versus 17.7 months for placebo plus beva­cizumab. Among HRD-positive patients without a BRCA mutation, the median PFS was 28.1 months with olaparib plus beva­cizumab and 16.6 months with placebo.

“This study reports the greatest hazard ratio [0.59] and longest progression-free survival we have ever seen. Patient selection was not restricted by surgical outcome or BRCA mutation status, so participants represent the general population of women with advanced ovarian cancer,” said lead investigator Isabelle L. Ray-Coquard, MD, PhD, Medical Oncology Department, Centre Léon Bérard, Lyon, France. “Prespecified subgroup analyses showed that patients with tumor BRCA mutations and patients with a positive HRD status had the greatest PFS benefits. These results reveal a patient population beyond tumor BRCA-mutated patients who are HRD-positive and experience substantial benefit from maintenance treatment with olaparib and beva­cizumab,” she added.

Grade ≥3 adverse events were reported in 57% of patients who received olaparib and 51% of patients who received placebo. Dose interruptions, reductions, and discontinuations were higher in the olaparib group. No clinically meaningful differences in quality of life were reported.

Study 3: VELIA/GOG-3005

This study enrolled 1140 patients with advanced, high-grade serous ovarian carcinoma earlier in the course of disease and evaluated the PARP inhibitor veliparib for maintenance therapy after first-line combination of veliparib plus carboplatin and paclitaxel. This is the first clinical trial to investigate the addition of first-line veliparib to front-line pac­litaxel plus carboplatin, with or without veliparib maintenance therapy.

Patients were included regardless of biomarker status and were randomized in a 1:1:1 ratio to chemotherapy plus placebo followed by placebo maintenance (ie, control arm); to chemotherapy plus veliparib followed by placebo maintenance; or to chemotherapy plus veliparib followed by veliparib main­tenance (ie, veliparib throughout). Again, bevacizumab was not part of the treatment regimen.

PFS was significantly expanded in the veliparib throughout group, and the magnitude of the PFS benefit was greater in patients with HRD-positive disease.

In the intent-to-treat analysis of the overall study, the median PFS was 23.5 months with veliparib as part of first-line therapy and maintenance therapy versus 17.3 months with placebo (P <.001). In the cohort with a BRCA mutation, the median PFS was 34.7 months with veliparib versus 22 months with placebo (P <.001); for patients with HRD-positive disease, the median PFS was 31.9 months versus 20.5 months, respectively (P <.001). PFS was not significantly improved in the veliparib plus chemotherapy arm with placebo maintenance versus controls.

Veliparib led to an increased incidence of anemia and thrombocytopenia when combined with chemotherapy, as well as overall nausea and fatigue.

“Veliparib added to carboplatin-­paclitaxel induction chemotherapy followed by veliparib maintenance therapy significantly extended PFS compared with induction chemotherapy alone in all patient cohorts in newly diagnosed high-grade, serous ovarian carcinoma, regardless of biomarker, choice of surgery, or paclitaxel regimen. We believe these data support veliparib administered during chemotherapy and continued as maintenance as a new standard of care,” said lead investigator Robert L. Coleman, MD, FACOG, FACS, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine, M.D. Anderson Cancer Center, Houston, TX. “It’s a great day for women with ovarian cancer seeking treatment.”

The results of this study were published online in the New England Journal of Medicine2 to coincide with the presentation at ESMO.

Remaining Questions

With these 3 studies identifying very active PARP inhibitors for first-line or maintenance therapy (after first-line chemotherapy) for patients with ovarian cancer, remaining questions include: Are there any meaningful differences between niraparib, olaparib, and veliparib? Should PARP inhibitors be used in all patients or just in those with BRCA mutations and HRD positivity? Should PARP inhibitors be used with chemotherapy? Or with immunotherapy? Are PARP inhibitors less toxic as maintenance treatment only? Is bevacizumab necessary at all?

References

  1. González-Martín A, Pothuri B, Vergote I, et al; for the PRIMA/ENGOT-OV26/GOG-3012 investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019 Oct 4. Epub ahead of print. 10.1056/NEJMoa1910962. Accessed October 30, 2019.
  2. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019 Sept 28. Epub ahead of print. 10.1056/NEJ Moa1909707. Accessed October 30, 2019.

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Last modified: March 6, 2020