PARP Maintenance Therapy Provides Varying Benefit in Advanced Ovarian Cancer

Eirwen M. Miller, MD

The benefit of PARP maintenance therapy for patients with advanced ovarian cancer differs depending on a number of factors, including the homologous recombination and BRCA mutation status of the tumor, 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