PAOLA-1 (NCT02477644) was a randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of Lynparza in combination with bevacizumab versus placebo/bevacizumab for the maintenance treatment of advanced high-grade epithelial ovarian cancer, fallopian tube or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab. Randomization was stratified by first-line treatment outcome (timing and outcome of cytoreductive surgery and response to platinum-based chemotherapy) and tBRCAm status, determined by prospective local testing. All available clinical samples were retrospectively tested with Myriad myChoice® CDx. Patients were required to have no evidence of disease (NED) due to complete surgical resection, or who were in complete response (CR), or partial response (PR) following completion of first-line platinum-containing chemotherapy and bevacizumab. Patients were randomized (2:1) to receive Lynparza tablets 300 mg orally twice daily in combination with bevacizumab (n=537) 15 mg/kg every three weeks or placebo/bevacizumab (n=269). Patients continued bevacizumab in the maintenance setting and started treatment with Lynparza after a minimum of 3 weeks and up to a maximum of 9 weeks following completion of their last dose of chemotherapy. Lynparza treatment was continued for up to 2 years or until progression of the underlying disease or unacceptable toxicity. Patients who in the opinion of the treating physician could derive further benefit from continuous treatment could be treated beyond 2 years. Treatment with bevacizumab was for a total of up to 15 months, including the period given with chemotherapy and given as maintenance. 

The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional efficacy endpoint was overall survival (OS).

A statistically significant difference in PFS was observed in the intent-to-treat (ITT) population. Planned exploratory analyses of PFS and OS were conducted in patients with known HRD status. The PFS hazard ratio (HR) for patients with HRD-negative tumors (277/806; 34%) was 1.00 (95% CI: 0.75, 1.34) and the OS HR was 1.18 (95% CI: 0.87, 1.60) indicating that the clinical benefit was primarily attributed to the results seen in the HRD-positive population. Efficacy results in patients with HRD-positive tumors are summarized in Table 19, Figure 2, and Figure 3. 

Among the 387 patients (48%) with HRD-positive tumors identified post-randomization using the Myriad myChoice® HRD Plus tumor test the median age was 58 years in both arms (range 32-82). Ovarian cancer was the primary tumor type in 87% of patients in both arms. Ninety five percent (95%) were serous histological type. The ECOG performance score was 0 in 75% of patients and 1 in 24% of patients. All patients had received first-line platinum-based therapy and bevacizumab. First-line treatment outcomes at screening indicated that patients had no evidence of disease with complete macroscopic resection at initial debulking surgery (36%), no evidence of disease/CR with complete macroscopic resection at interval debulking surgery (29%, both arms), no evidence of disease/CR in patients who had either incomplete resection (at initial or interval debulking surgery) or no debulking surgery (16%, both arms) and patients with a partial response (19%, both arms). Sixty-two (62%) of patients in the Lynparza/bevacizumab arm and 58% of patients in placebo/bevacizumab arm had tumors with a deleterious BRCA mutation. Patients were not restricted by the surgical outcome with 67% having complete cytoreduction at initial or interval debulking surgery and 33% having residual macroscopic disease.

Figure 2 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – PAOLA-1 (HRD-positive status)

Figure 3 Kaplan-Meier Curves of Overall Survival – PAOLA-1 (HRD-positive status)*

* Based on final OS subgroup analysis.