HRD, BRCA Status May Inform PARP Inhibitor Suitability in Advanced Ovarian Cancer

Eirwen M. Miller, MD

For patients with advanced ovarian cancer, the homologous recombination and BRCA mutation status of their tumor may clue providers into whether a PARP inhibitor is appropriate as maintenance therapy for that individual, according to Eirwen M. Miller, MD.¹

In a presentation delivered at the 40th Annual CFS®, Miller outlined findings from 5 clinical trials that evaluated the safety and efficacy of PARP inhibition therapy: SOLO-1 (NCT01844986), PRIMA (NCT02655016), ATHENA-MONO (NCT03522246), PAOLA-1 (NCT02477644), and Ovario (NCT03326193).

“Each of these studies evaluated PARP inhibitor maintenance either as a single agent or in combination with bevacizumab [Avastin] for patients with stage III to IV ovarian cancer following a complete or partial response to platinum-based chemotherapy,” Miller, a gynecologic oncologist at Allegheny Health Networks in Pittsburgh, Pennsylvania, said during the presentation. “The inclusion criteria vary somewhat across these studies. [Although] cross-trial comparison is really tempting, it’s not valid.”

In the phase 3 SOLO-1 trial, investigators examined the efficacy of olaparib (Lynparza) maintenance therapy in patients with newly diagnosed stage III or IV ovarian cancer harboring a mutation in BRCA1, BRCA2, or both. Patients were randomly assigned 2:1 to oral olaparib 300 mg twice daily (n = 260) or placebo (n = 131). The primary end point of the study was progression-free survival (PFS).²

In the overall study population, most patients (83%) had stage III disease. A majority of patients (82%) achieved a complete response (CR) after treatment with chemotherapy. Nearly all patients had high-grade serous ovarian cancer (HGSOC; 97%). All patients had homologous recombination deficiency (HRD)-positive disease.

Findings from the trial showed that olaparib maintenance therapy provided a clear PFS benefit over placebo; the median PFS was 56.0 months vs 13.8 months, respectively (HR, 0.33; 95% CI, 0.25-0.43). Additionally, the median overall survival (OS) was not reached (95% CI, NR-NR) in the olaparib arm compared with 75.2 months (95% CI, 65.4-NR) in the placebo arm (HR, 0.55; 95% CI, 0.40-0.76).³

Miller highlighted key safety findings from SOLO-1. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) were adverse effects (AEs) of special interest. In the primary PFS analysis, 3 patients treated with olaparib eventually developed MDS or AML vs no patients in the placebo arm. After a 7-year follow-up, in the final OS analysis, 4 cases of MDS/AML were reported in the investigational arm and 1 case was reported in the placebo arm.

The phase 3 PRIMA trial compared the efficacy of niraparib (Zejula) maintenance therapy with placebo in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy. Patients were randomly assigned 2:1 to receive either niraparib or placebo once daily. The primary end point was PFS.⁴

A slight majority of patients (50.8%) were HRD positive. Patients were HRD positive with BRCA mutations at a rate of 30.4%. HRD positivity and BRCA wild-type status was reported in 20.5% of patients. Stage IV disease was reported in 35% of patients. Most experienced a CR after chemotherapy (70%), and had HGSOC histology (94%).

In regard to the primary outcome, patients with BRCA-mutant disease treated with niraparib had a median PFS of 22.1 months compared with 10.9 months with placebo (HR, 0.40; 95% CI, 0.27-0.62).5 Patients with HRD-positive disease had a median PFS of 21.9 months vs 10.4 months, respectively (HR, 0.43; 95% CI, 0.31-0.59). Among those with HRD-positive, BRCA wild-type disease, the median PFS was 19.6 months compared with 8.2 months, respectively (HR, 0.50; 95% CI, 0.31-0.83). Those with HRD-negative disease experienced a median PFS of 8.1 vs 5.4 months, respectively (HR, 0.68; 95% CI, 0.49-0.94). In the overall intention-to-treat (ITT) population, patients who received niraparib (n = 487) achieved a median PFS of 13.8 months vs 8.2 months for patients in the placebo arm (n = 246; HR, 0.62; 95% CI, 0.50-0.76).⁴

Additionally, treatment with niraparib had an effect on OS: The 24-month OS rate was 84% in the investigational arm compared with 77% in the placebo arm (HR, 0.70; 95% CI, 0.44-1.11). More specifically, patients with HRD-positive disease experienced 24-month OS rates of 91% vs 85%, respectively (HR, 0.61; 95% CI, 0.27-1.39). Patients with HRD-negative disease had a 24-month OS of 81% vs 59%, respectively (HR, 0.51; 95% CI, 0.27-0.97). Miller noted that these figures were based on 11% maturity at interim analysis.

Rucaparib (Rubraca) maintenance therapy was compared to placebo for patients with stage III to IV high-grade ovarian cancer undergoing surgical cytoreduction in the phase 3 ATHENA-MONO trial. Patients were randomly assigned 4:1 to received oral rucaparib 600 mg twice daily (n = 427) or placebo (n = 111). The primary end point was PFS.⁵

In the overall population, patients had HRD-positive disease, HRD-positive disease with BRCA mutation, HRD-positivity with BRCA wild-type disease, and HRD-negative disease at a rate of 43.5%, 21.4%, 22.1%, and 44.2%, respectively. Most patients had HGSOC histology (91%), stage III disease (75%), and experienced a CR following chemotherapy (75%).

In the ITT population, patients experienced a median PFS of 20.2 months vs 9.2 months in the investigational and placebo arms, respectively (HR, 0.52; 95% CI, 0.40-0.68). Patients with BRCA-mutant disease achieved a median PFS of NR vs 14.7 months, respectively (HR, 0.40; 95% CI, 0.21-0.75). Among patients with HRD-positive disease, the median PFS was 28.7 months compared with 11.3 months, respectively (HR, 0.47; 95% CI, 0.31-0.72). Patients with BRCA wild-type, HRD-positive disease experienced a median PFS of 20.3 months vs 9.2 months, respectively (HR, 0.58; 95% CI, 0.33-1.01). Finally, patients who were HRD negative had a median PFS of 12.1 vs 9.1 months, respectively (HR, 0.65; 95% CI, 0.45-0.95).

Miller noted that the OS figures in ATHENA-MONO are to be determined.

Investigators combined olaparib with bevacizumab as maintenance therapy for patients withnewly diagnosed, advanced, high-grade ovarian cancer who responded to first-line chemotherapy in the phase 3 PAOLA-1 trial. Patients were eligible irrespective of surgical outcome or BRCA mutation status. Patients were randomly assigned 2:1 to receive olaparib 300 mg twice daily (n = 537) or placebo (n = 269). Every patient received bevacizumab 15 mg/kg every 3 weeks for up to 15 months.⁶

Patients in PAOLA-1 had HRD-positive disease, HRD-positive disease with a BRCA mutation, HRD-positive/BRCA wild-type disease, and HRD-negative disease at a rate of 48.0%, 29.4%, 18.6%, and 34.3%, respectively. Most patients had HGSOC histology (96%) and stage III disease (70%), and had no evidence of disease (53%) after treatment with chemotherapy.

In the overall population, the median PFS was 22.1 months in the investigational arm compared with 16.6 months in the control arm (HR, 0.59; 95% CI, 0.49-0.72). Patients with BRCA-mutant disease experienced a median PFS of 37.2 months compared with 21.7 months, respectively (HR, 0.31; 95% CI, 0.20-0.47). Patients with HRD-positive disease achieved a median PFS of 37.2 months vs 17.7 months (HR, 0.33; 95% CI, 0.25-0.45). Those with HRD-positive, BRCA wild-type ovarian cancer registered a median PFS of 28.1 months vs 16.6 months (HR, 0.43; 95% CI, 0.28-0.66). Finally, those with HRD-negative disease experienced a median PFS of 16.6 months vs 16.2 months, respectively (HR, 1.00; 95% CI, 0.75-1.35).⁶

Regarding OS, the median in the overall population was 56.5 months vs 51.6 months in the combination and placebo arms, respectively (HR, 0.92; 95% CI, 0.76-1.12). For patients with BRCA-mutant disease, the median OS was 75.2 months vs 66.9 months, respectively (HR, 0.60; 95% CI, 0.39-0.93). Those with HRD-positive disease experienced a median OS of 75.2 vs 57.3 months, respectively (HR, 0.62; 95% CI, 0.45-0.85).

Notably, for patients with HRD-positive, BRCA wild-type disease the median OS was NR vs 52 months, respectively (HR, 0.71; 95% CI, 0.45-1.13). No OS benefit was observed with the combination for patients with HRD-negative disease; the median OS was 36.8 months in the combination arm compared with 40.4 months in the placebo arm (HR, 1.19; 95% CI, 0.88-1.63).⁷

Miller also presented safety findings for the AEs of special interest from PAOLA-1. At the primary PFS analysis, 7 patients in the combination arm experienced MDS/AML compared with 3 in the placebo arm. At the final OS analysis these figures were 22 patients vs 8 patients, respectively.

In the phase 2 Ovario trial, niraparib plus bevacizumab was evaluated as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer. The primary end point was PFS.⁸

Patients in Ovario had HRD-positive disease, HRD-positive disease with BRCA mutation, HRD-positive/BRCA wild-type, and HRD-negative disease at a rate of 46.7%, 27.6%, 15.2%, and 36.2%, respectively. Most patients had HGSOC histology (95%) and stage III disease (78%), and achieved a CR after treatment with chemotherapy (58%).

Among 105 efficacy-evaluable patients the median PFS of 19.6 months (95% CI, 16.5-25.1). The median PFS was 28.3 months, 28.3 months, and 14.2 months in the HRD-positive, HRD-positive/BRCA wild-type, and HRD-negative subgroups, respectively.

OS data for Ovario was not available, said Miller.

“There remains a significant unmet need for HRD-negative tumors,” Miller said. “We anxiously await the results from FIRST [NCT03602859], DUO-O [NCT03737643], and KEYLYNK [NCT03740165], in which PARP inhibitors have been combined with immunotherapy in the maintenance setting. There are also ongoing trials evaluating novel maintenance therapy agents including an anti-Ca125 monoclonal antibody and antibody drug conjugates targeting the folate receptor alpha and NaPi2b.”

References

1. Miller EN. Evolving Landscape of frontline maintenance therapy for advanced ovarian cancer. Presented at: 40th Annual CFS®: November 9-11, 2021; New York, NY.
2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858
3. DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 Trial. J Clin Oncol. 2022;JCO2201549. doi:10.1200/JCO.22.01549
4. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962
5. Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45) J Clin Oncol. 2022;JCO2201003. doi:10.1200/JCO.22.01003
6. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361
7. Ray-Coquard I, Leary A, Pignata S, et al. Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC). Ann Oncol. 2022;33(suppl 7):S1396-1397. doi:10.1016/j.annonc.2022.08.025
8. Hardesty MM, Krivak TC, Wright GS, et al. OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. Gynecol Oncol. 2022;166(2):219-229. doi:10.1016/j.ygyno.2022.05.020