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Optimizing benefits of PARP inhibition in first-line maintenance of newly diagnosed ovarian cancer

Prof. Charlie Gourley
University of Edinburgh
United Kingdom
30 Sep 2020
First-line poly(ADP-ribose)polymerase (PARP) inhibitor maintenance therapy significantly increases progression-free survival (PFS) in high-grade ovarian cancer patients. However, questions remain regarding the ability of PARP inhibitors to increase the cure rate, the types of patients most likely to benefit from them, and when it is best to employ them. In a virtual small-group meeting with experts in Hong Kong, Professor Charlie Gourley of the University of Edinburgh, Edinburgh, UK discussed the criteria for optimal patient selection and the positioning of PARP inhibitors in the patient journey.

Unprecedented PFS improvement with olaparib

The international, double-blind, phase III SOLO-1 trial randomized 391 women with newly diagnosed, BRCA-mutated (BRCAmut), stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer to receive olaparib (300 mg tablet BID) or placebo in a 2:1 ratio. [N Engl J Med 2018;379:2495-2505]

“SOLO-1 patients can be described as a favourable-risk group, as 82 percent had complete response to preceding chemotherapy and would be expected to perform well regardless of further therapy,” said Gourley. However, 20 percent of patients receiving placebo had progressed within 12 months of diagnosis, having received surgery and chemotherapy, indicating a relapse within a platinum-resistant timeframe.

“Therefore, 20 percent of patients would not be eligible to receive a PARP inhibitor following second-line maintenance. This represents one of the arguments for using PARP inhibitors as first-line maintenance,” commented Gourley.

After a median follow-up of 41 months, the risk of disease progression or death was 70 percent lower with olaparib vs placebo (3-year PFS rate estimate, 60 percent vs 27 percent; hazard ratio [HR], 0.30; 95 percent confidence interval [CI], 0.23 to 0.41; p<0.001).

“The median PFS benefit of first-line maintenance with olaparib was approximately 36 months – a benefit larger than what was previously reported in any other first-line trial [within this population],” said Gourley.

The HRs for secondary efficacy endpoints of median time to first (0.30; 95 percent CI, 0.22 to 0.40; p<0.0001) and second subsequent therapy or death (0.45; 95 percent CI, 0.32 to 0.63; p<0.0001) and median second PFS (0.50; 95 percent CI, 0.35 to 0.72; p<0.001) all favoured olaparib maintenance. “These findings suggest that olaparib’s benefit extends beyond delaying the first disease progression,” commented Gourley. “The question regarding first-line olaparib’s potential to increase the cure rate is likely to be addressed by the overall survival [OS] data expected in about a year’s time.”

Olaparib + bevacizumab maintenance extends PFS, regardless of BRCA status

The international, double-blind, phase III PAOLA-1 trial randomized 806 women with newly diagnosed, advanced, high-grade ovarian cancer to receive olaparib (300 mg BID, for ≤24 months) or placebo in addition to bevacizumab (15 mg/kg, Q3W, for ≤15 months). [N Engl J Med 2019;381:2416-2428]

After a median follow-up of 22.9 months, the median PFS was 22.1 months with olaparib plus bevacizumab vs 16.6 months with placebo plus bevacizumab in the intention-to-treat population (HR, 0.59; 95 percent CI, 0.49 to 0.72; p<0.001). “In the absence of an olaparib-only arm, it is difficult to interpret the role of bevacizumab in this trial,” commented Gourley.

In patients with homologous recombination-deficient (HRD) tumours, including those with BRCA mutations, the HR was 0.33 (95 percent CI, 0.25 to 0.45) in favour of adding olaparib to bevacizumab maintenance, with a median PFS of 37.2 months vs 17.7 months in the olaparib vs placebo group. In HRD-positive patients without BRCA mutations, the HR was 0.43 (95 percent CI, 0.28 to 0.66), and the median PFS was 28.1 months vs 16.6 months.

“No benefit was observed in the HRD-negative group, which is in contrast to the findings of prior trials that reported treatment benefits associated with PARP inhibition in recurrent and newly diagnosed ovarian cancer, regardless of HRD status,” noted Gourley. [N Engl J Med 2016;375:2154-2164; Lancet 2017;390:1949-1961; N Engl J Med 2019; 381:2391-2402]

Niraparib maintenance improves PFS in poor-risk patients, regardless of BRCA status

The international, double-blind, phase III PRIMA trial randomized 733 women with newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer to receive niraparib (200 mg or 300 mg QD) or placebo for 36 months or until disease progression. [N Engl J Med 2019;381:2391-2402]

Among patients with HRD-positive tumours, the median PFS was significantly longer in the niraparib vs placebo group (21.9 months vs 10.4 months; HR, 0.43; 95 percent CI, 0.31 to 0.59; p<0.001). “For BRCAmut patients, the HR was 0.40 [95 percent CI, 0.27 to 0.62; p<0.001]. For BRCA wild-type patients with HRD-positive tumours, the HR was 0.50 [95 percent CI, 0.31 to 0.83; p=0.006]. Patients with HRD-negative tumours also appeared to benefit from niraparib maintenance, with a HR of 0.68 [95 percent CI, 0.49 to 0.94; p=0.020],” reported Gourley.

At the 24-month interim analysis, OS rate was 84 percent in the niraparib group vs 77 percent in the placebo group (HR, 0.70; 95 percent CI, 0.44 to 1.11). [N Engl J Med 2019;381:2391-2402] “In view of the poor risk of PRIMA patients, the final OS data would indicate whether niraparib maintenance cures more patients. The data may be available in the near future,” commented Gourley. “However, it is unclear how these results would translate to better-risk patients.”

Key messages and unanswered questions

First-line PARP inhibitor maintenance therapy significantly increases PFS and second PFS in high-grade ovarian cancer patients. “All patients with germline or somatic BRCA mutations should be considered for PARP inhibitor therapy,” advised Gourley.

Outside of BRCA mutations, HRD testing provides some indication of the most likely responders. “However, the findings are not consistent across trials, and both false-negative and false-positive results remain a problem. Elucidating PARP inhibitor resistance mechanisms may help optimize the molecular tools for patient selection and maximize the utility of these therapies,” noted Gourley. “The first-line studies considered heterogeneous populations and some combined a PARP inhibitor with bevacizumab; it remains to be seen whether the results translate outside of each particular trial population.”

“In Study 19, relapsed patients were most likely to be super-responders to olaparib if they had a complete response to their preceding chemotherapy, meaning that the PARP inhibitor was given in the context of minimal residual disease, thereby minimizing the possibility of any resistant tumour cells,” said Gourley. [J Clin Oncol 2017;35(Suppl):5533] “Additionally, in the SOLO-1 trial, patients with or without residual disease had improved outcomes on olaparib vs placebo. However, those with no evidence of residual disease [HR, 0.33; 95 percent CI, 0.23 to 0.46] were even more likely to benefit from olaparib than those with residual disease [HR, 0.44; 95 percent CI, 0.25 to 0.77].” [Matthews CA, et al, ASCO 2019, poster 5541]

In terms of positioning in the patient journey, SOLO-1 and SOLO-2 data indicate that the greatest benefit is derived from using olaparib as first-line maintenance treatment. “While the two trials yielded identical HRs of 0.30 in favour of olaparib after first-line or second-line chemotherapy, the absolute PFS improvement with first-line olaparib was substantially greater than that in the relapsed disease setting [36 months vs 13.6 months],” highlighted Gourley. (Figure)

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Most Read Articles
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