Success for First-Line PARP Inhibition in Ovarian Cancer Free

Three phase III trials make a strong case for using PARP inhibitors as first-line maintenance therapy for women with advanced ovarian cancer and suggest that patients other than those with BRCA1/2 mutations may benefit from these drugs. The potentially practice-changing data were disclosed during the ESMO Congress 2019 in Barcelona, Spain, September 27–October 1.

For newly diagnosed high-grade ovarian cancer, the standard of care has long been surgery and platinum chemotherapy, followed by maintenance with bevacizumab (Avastin; Genentech), or active surveillance. PARP inhibitors, having already “revolutionized the treatment landscape” for recurrent ovarian cancer, began their foray into the first-line spotlight last year, said Susana Banerjee, MD, of the Royal Marsden Hospital in London, UK.

Then, the phase III SOLO-1 study showed that compared with placebo, maintenance olaparib (Lynparza; AstraZeneca) considerably improved progression-free survival (PFS) among women with BRCA mutations who were responsive to initial chemotherapy. Shortly after SOLO-1 was presented at the 2018 ESMO Congress, olaparib became the first of three FDA-approved PARP inhibitors to earn a first-line maintenance indication for these patients.

In Barcelona, Antonio González-Martín, MD, of Clínica Universidad de Navarra in Madrid, Spain, highlighted results from the concurrently published PRIMA trial, in which 728 patients responsive to chemotherapy were randomized 2:1 to receive maintenance niraparib (Zejula; Tesaro) or placebo. The median PFS was 13.8 months and 8.2 months, respectively. Among the subset of 373 patients who tested positive for homologous repair deficiency (HRD), PFS increased to 21.9 months, independent of BRCA status. Notably, even HRD-negative patients benefited from maintenance niraparib, which reduced their risk of disease progression or death by 32%.

The PAOLA-1 trial built on SOLO-1, evaluating olaparib alongside bevacizumab as first-line maintenance therapy. Researchers randomized 806 patients 2:1 to receive maintenance olaparib or placebo on top of bevacizumab. Isabelle Ray-Coquard, MD, of Université Claude Bernard in Lyon, France, reported that the median PFS was 22.1 months versus 16.6 months. With a median time of 7 months from the first cycle of chemotherapy to randomization, these results meant that those in the olaparib arm “experienced nearly 30 months without relapse,” Ray-Coquard noted. Olaparib showed increased efficacy in HRD-positive patients, regardless of BRCA status: Subgroup analyses indicated median PFS times of 37.2 months and 28.1 months for BRCA-mutant and BRCA–wild-type patients, respectively. Contrary to PRIMA, patients who were HRD-negative did not benefit significantly from maintenance olaparib.

Discussing both trials, Ana Oaknin, MD, of Vall d'Hebron Institute of Oncology in Barcelona, opined that “the robust reduction in progression risk strongly justifies moving PARP inhibitors to the first-line setting.” She pointed out that because PAOLA-1's results “were consistent with the benefit seen in SOLO-1, with olaparib monotherapy,” bevacizumab's contribution to the overall efficacy remains to be determined. Another question Oaknin believes is worth probing: Why HRD-negative patients in the two studies had different responses to PARP inhibition.

The VELIA trial took a slightly different approach: 757 untreated patients were randomly assigned to receive paclitaxel/carboplatin combined with veliparib (AbbVie), then maintenance veliparib; or just chemotherapy with placebo, followed by maintenance placebo. Robert Coleman, MD, of The University of Texas MD Anderson Cancer Center in Houston, reported that the median PFS was 23.5 months and 17.3 months, respectively. Veliparib's benefit was most pronounced in patients with HRD-positive, BRCA-mutant disease; the median PFS increased to 34.7 months. No significant improvement was seen in the HRD-negative subset.

Published concurrently with the presentation, VELIA is the first trial to show that administering a PARP inhibitor alongside chemotherapy—historically challenging due to hematologic toxicity—can be safely done, Coleman said. However, Mansoor Mirza, MD, of Rigshospitalet in Copenhagen, Denmark, noted that “without a study arm assessing veliparib in maintenance only, we don't know if its up-front combination with chemotherapy is necessary for the benefit observed.”

Taking these studies together, “we now know that we can use PARP inhibitors first-line, and not just for women with BRCA mutations,” Banerjee concluded. “Next, we'll need to be ready in clinical practice to deliver HRD testing to all patients, and perhaps decide on a standard method.” –Alissa Poh