CA-125 Level Informs Surveillance Strategy for Olaparib/Bevacizumab in Ovarian Cancer

Sakari Hietanen, MD, PhD

CA-125 surveillance alone could be used to detect disease progression in patients with advanced ovarian cancer and an abnormal CA-125 level at the beginning of frontline maintenance therapy with olaparib (Lynparza) and bevacizumab (Avastin), according to an analysis from the phase 3 PAOLA-1 that was presented at the SGO 2021 Annual Meeting on Women’s Cancer.

Additional data from the analysis showed that patients who have a normal baseline CA-125 level could benefit from concomitant imaging and CA-125 surveillance.

Of 462 patients in the intention-to-treat (ITT) population with Response Evaluation Criteria in Solid Tumors (RECIST) progression, 39% had RECIST progression alone and 45% had CA-125 progression before RECIST progression, with a 2.4-month median time between CA-125 and RECIST progression. The remaining patients (16%) had CA-125 progression at the same time as reported RECIST progression.

In patients with an abnormal baseline CA-125 level (n = 89), 16.9% had RECIST progression alone, 16.9% had CA-125 progression concomitant to RECIST progression, and 66.3% had CA-125 progression before RECIST progression. In patients with a normal baseline CA-125 level (n = 372), 44.4% had RECIST progression alone, 16.1% had CA-125 progression concomitant to RECIST progression, and 39.5% had CA-125 progression before RECIST progression.

“Only 17% of patients with abnormal baseline CA-125 levels at the start of maintenance therapy had RECIST progression alone compared with 44% of patients with normal baseline CA-125 levels [P <.001]. This suggests that the baseline CA-125 level when patients start maintenance therapy with olaparib plus bevacizumab may guide subsequent follow-up methods,” said lead study author Sakari Hietanen, MD, PhD, an associate professor, and chief of the Department of Obstetrics and Gynecology at Turku University Hospital, in Turku, Finland, in a virtual presentation of the data.

Limited evidence has shown the utility of using serum CA-125, a surrogate biomarker for disease progression, to identify relapse in patients receiving a PARP inhibitor as maintenance therapy. To that end, investigators evaluated progression per RECIST v1.1 criteria/CA-125 to determine the role of CA-125 as a potential surveillance marker in PAOLA-1.

In the PAOLA-1 trial, patients with newly diagnosed International Federation of Gynecology and Obstetrics stage III/IV, high-grade serous or endometrioid ovarian, fallopian tube and/or primary peritoneal cancer who had received up-front or interval surgery, platinum/taxane-based chemotherapy, and at least 2 cycles of bevacizumab were randomized 2:1 to receive 300 mg of olaparib twice daily for 2 years plus bevacizumab or placebo plus bevacizumab.

Primary results showed that olaparib plus bevacizumab led to a statistically significant improvement in PFS as a first-line maintenance therapy vs bevacizumab alone following first-line platinum-based chemotherapy in patients with advanced ovarian cancer.

In the overall population, the median PFS was 22.1 months with olaparib/bevacizumab vs 16.6 months with placebo/bevacizumab (HR, 0.59; 95% CI, 0.49-0.72; P <.001). In patients with homologous recombination deficiency (HRD), defined as a BRCA1/2 mutation and/or a genomic instability score of at least 42, the median PFS was 37.2 months with olaparib/bevacizumab vs 17.7 months with placebo/bevacizumab (HR, 0.33; 95% CI, 0.25-0.45).

“In the primary PAOLA-1 analysis, adding olaparib to maintenance bevacizumab provided a significant PFS benefit based on RECIST criteria according to investigator assessment. A significant PFS benefit provided by olaparib plus bevacizumab vs placebo plus bevacizumab was consistent with that reported in the primary analysis [with extended follow-up],” said Hietanen.

Time from randomization to earliest progression by RECIST, CA-125, or death served as a secondary end point of PAOLA-1. Tumor assessment scans were performed every 24 weeks, or every 12 weeks if there was evidence of clinical or CA-125 progression. CA-125 levels were assessed every 12 weeks.

CA-125 progression was defined as a CA-125 level at least 2 times the nadir value of patients with abnormal pretreatment levels or the upper limit of normal level of patients with normal pretreatment/normalized levels on 2 occasions at least 1 week apart. CA-125 progression before RECIST progression was defined as CA-125 progression more than 7 days before RECIST progression. CA-125 progression concomitant to RECIST progression was defined as CA-125 progression 7 or fewer days before or after RECIST progression.

The median follow-up for PFS assessed by RECIST/CA-125 was 24.2 months in the olaparib/bevacizumab arm (n = 537) vs 24.7 months in the placebo/bevacizumab arm (n = 269). The median PFS was consistent with the primary analysis, at 22.1 months in the olaparib/bevacizumab arm vs 15.4 months in the placebo/bevacizumab arm using time to earliest progression by RECIST, CA-125, or death (HR, 0.58; 95% CI, 0.48-0.70). The 2-year PFS rates were 47% and 28%, respectively.

Additional findings indicated that baseline CA-125 levels provided a more accurate picture of which patients could be monitored by CA-125 levels alone vs imaging plus CA-125 levels compared with HRD status.

In HRD-positive patients (n = 171), 45.0% had RECIST progression alone, 15.8% had CA-125 progression concomitant to RECIST progression, and 39.2% had CA-125 progression before RECIST progression. In HRD-negative/unknown patients (n = 291), 35.7% had RECIST progression alone, 16.5% had CA-125 progression concomitant to RECIST progression, and 47.8% had CA-125 progression before RECIST progression.

When CA-125 progression was identified prior to RECIST progression, the median time between CA-125 and RECIST progression was 2.4 months (range, 1.2-4.7) in the ITT population (n = 206), 2.0 months (range, 1.2-4.1) in the HRD-positive population (n = 67), and 2.2 months (range, 1.3-5.5) in the HRD-negative population (n = 95). In the HRD-unknown group (n = 44), the median time was 2.8 months (range, 1.1-5.1). In patients with a normal baseline CA-125 level (n = 147), the median time was 2.5 months (range, 1.3-4.7). In patients with an abnormal baseline CA-125 level, the median time was 2.1 months (range, 1.1-5.3).

In patients with BRCA mutations who received olaparib/bevacizumab, 55.3% had RECIST progression alone, 2.6% had CA-125 progression concomitant to RECIST progression, and 42.1% had CA-125 progression before RECIST progression. In patients with BRCA mutations who received placebo/bevacizumab, 43.5% had RECIST progression alone, 17.4% had CA-125 progression concomitant to RECIST progression, and 39.1% had CA-125 progression before RECIST progression.

In patients with wild-type BRCA who received olaparib/bevacizumab, 37.3% had RECIST progression alone, 15.7% had CA-125 progression concomitant to RECIST progression, and 47.0% had CA-125 progression before RECIST progression. In patients with wild-type BRCA who received placebo/bevacizumab, 36.6% had RECIST progression alone, 20.4% had CA-125 progression concomitant to RECIST progression, and 43.0% had CA-125 progression before RECIST progression.

Reference

Hietanen S, Pautier P, Harter P, et al. RECIST/CA-125 progression-free survival and the role of CA-125 surveillance in the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high‐grade ovarian carcinoma. Presented at: SGO Annual Meeting; March 19-25, 2021; virtual. Abstract 10542.