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BARCELONA -- Patients with newly diagnosed advanced ovarian cancer who responded to first-line chemotherapy, then were treated with niraparib (Zejula), had a significantly reduced risk of disease recurrence or death versus placebo, a researcher reported here.

In the PRIMA study, treatment with niraparib was associated with a hazard ratio of 0.62 (95 CI 0.5-0.75, P<0.0001) for disease progression among the overall population of women who achieved either a complete or partial response to platinum-based chemotherapy, according to Antonio Gonzalez-Martin, MD, of the Clinica Universidad de Navarra in Madrid.

That translated to a median progression-free survival (PFS) in the overall study population of 13.8 months (95% CI 11.5-14.9) for the 487 women assigned to receive niraparib compared with a median PFS of 8.2 months (95% CI 7.3-8.5) among the 246 women assigned to placebo (P<0.001), said Gonzalez-Martin in a presentation at the European Society for Medical Oncology (ESMO) annual meeting.

In a second study presented at ESMO, veliparib integrated with first-line chemotherapy, then continued as maintenance treatment, significantly extended PFS regardless of response to first-line treatment. In women with high-grade serous ovarian cancer, frontline combination of veliparib, carboplatin, and paclitaxel, followed by maintenance veliparib monotherapy, led to a 32% reduction in the risk of progression or death versus placebo plus chemotherapy with placebo maintenance, reported Robert Coleman, MD, of the MD Anderson Cancer Center in Houston.

Both studies were simultaneously published in the New England Journal of Medicine.

PRIMA

The double-blind, placebo-controlled of niraparib was done in patients that had been newly diagnosed with advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer.

Eligible patients had achieved complete response (CR) or partial response (PR) to first-line platinum-based chemotherapy. The trial excluded women who had complete primary debulking surgery. Stratification factors included:

• Best response to the first-line chemotherapy (CR vs PR)
• Receipt of neoadjuvant chemotherapy (yes vs no)
• Homologous-recombination deficiency (HRD) status (positive vs negative vs unknown per )

Patients were about age 62; about 65% had stage III disease while stage IV was reported in 35%; about 70% achieved CR after chemotherapy while around 30% achieved PR; about half had HRD status; and 67% received neoadjuvant chemotherapy.

Patients were randomized to receive 300 mg oral niraparib or placebo once daily.

Gonzalez-Martin reported that patients in the HRD-positive subgroup saw particular benefits, with a PFS of 21.9 months (95% CI 19.3-NR) versus 10.4 months (95% CI 8.1-12.1) in the respective treatment arms (HR 0.43, 95% CI 0.31–0.59, P<0.0001).

At the 24-month interim analysis, overall survival (OS) was 84% in the niraparib group and 77% in the placebo group (HR 0.70, 95% CI 0.44-1.11).

The most common grade ≥3 adverse events were anemia (31.0%), thrombocytopenia (28.7%), and neutropenia (12.8%). No treatment-related deaths occurred.

"The most common treatment-emergent averse event was reversible myelosuppression," Gonzalez-Martin reported. "One patient on niraparib was diagnosed with myelodysplastic syndrome after 9 months of therapy."

He noted that at the time of ESMO presentation, 37% of the patients are still on niraparib versus 28% of patients on placebo.

"Niraparib monotherapy after first line platinum-based chemotherapy should be considered a new standard of care," Gonzalez-Martin said. "Niraparib is the first PARP inhibitor to demonstrate benefit in patients across biomarkers subgroups after platinum-based chemotherapy in frontline, consistent with prior clinical studies of niraparib in recurrent ovarian cancer."

VELIA

The randomized 1,140 patients into three arms:

• Control: carboplatin and paclitaxel with placebo followed by placebo as maintenance (n=375)
• Veliparib-combination-only: 150 mg veliparib twice daily plus carboplatin and paclitaxel as induction therapy followed by placebo maintenance (n=383)
• Veliparib-throughput: 150 mg veliparib twice daily to carboplatin and paclitaxel followed by veliparib alone at 400 mg twice daily as maintenance (n=382)

Combination chemotherapy was six cycles, and maintenance therapy was 30 additional cycles, according to Coleman and colleagues.

Median patient age was 62; about 60% had an ECOG performance status 0; about 66% had stage III disease; and nearly 50% had no residual disease while about 30% had residual disease. Most had received primary surgery.

The authors reported that, in the intention-to-treat (ITT) population, the PFS was 23.5 months in the veliparib-throughput group versus 17.3 months in the control group (HR 0.68, 95% CI 0.56-0.83, P<0.001).

In the BRCA-mutation cohort, the median PFS was 34.7 months in the veliparib-throughout group versus 22.0 months in the control group (HR for progression or death 0.44, 95% CI 0.28-0.68, P<0.001).

And in the HRD cohort, median PFS was 31.9 months in the veliparib-throughput group versus 20.5 months in the control group (HR 0.57, 95 CI 0.43-0.76, P<0.001).

The veliparib-chemotherapy combination led to a higher incidence of anemia, thrombocytopenia, nausea, and fatigue overall, the authors stated.

They also noted that "the data regarding [OS] were not sufficiently mature in the BRCA-mutation cohort, the HRD cohort, and the [ITT] population, with percentages of required end points of 21%, 24%, and 49%, respectively. Because of the testing hierarchy, [OS] in the veliparib-throughout group as compared with the control group cannot be tested until a sufficient number of events have occurred, so formal hypothesis testing of [PFS] in the veliparib combination-only group as compared with the control group has not been performed."

Still, "Veliparib in combination with chemotherapy should be considered a new treatment option for women with newly diagnosed, advanced stage serous ovarian cancer," Coleman stated.

Put PARP First

ESMO discussant Ana Oaknin, MD, PhD, of the Vall d'Hebron University Hospital, Barcelona, said that with PRIMA, and other trial results "We are witnessing a paradigm shift in the first-line treatment for advanced ovarian disease...in those patients who have achieved a partial response of a complete response following platinum therapy, PARP inhibitor agents as a maintenance therapy significantly improve progression-free survival."

She added that PRIMA, along with other studies at ESMO, demonstrated that niraparib treatment does not have a negative impact on quality of life, and that with some biomarkers "there is a robust reduction in risk of progression that strongly justify moving PARP inhibitors to first line."

ESMO discussant Mansoor Raza Mirza, MD, of Rigshospitalet of Copenhagen University, stated that "VELIA demonstrated clinically significant benefit of chemotherapy plus veliparib followed by veliparib maintenance in the BRCA mutant population...the time has come for all patients to have a PARP inhibitor."