Results from PARP inhibitor trials point to drastic changes for ovarian cancer management

What ESMO 2019 announcements mean for the future of the ovarian cancer market and patient care

PARP inhibitors have shown extremely encouraging data that could help pave the way for an entirely new treatment algorithm in ovarian cancer. These agents have given patients the opportunity for more effective treatments in the frontline and recurrent settings. Therefore, we predict PARP inhibitors will be the most successful drug class in ovarian cancer, capturing 41% of the market share in 2028 in the major-markets.

AstraZeneca/Merck & Co’s Lynparza (olaparib), GlaxoSmithKline’s Tesaro (niraparib), and AbbVie’s veliparib captured the biggest headlines of ESMO 2019 Congress with results released of the PAOLA-1, PRIMA, and VELIA trial, respectively, in ovarian cancer.

We expect that Lynparza in combination with Avastin maintenance, as well as Zejula maintenance will drastically change the front-line management of advanced ovarian cancer, regardless of the patients’ BRCA status.

In the below post, we review the results from the PAOLA-1, PRIMA, and VELIA trial and how these results will impact the management of newly diagnosed advanced ovarian cancer.

PAOLA-1 trial: Adding Lynparza to Avastin maintenance demonstrates substantial clinical benefit in newly diagnosed advanced ovarian cancer

Results from the PAOLA-1 trial were eagerly anticipated following AstraZeneca/Merck & Co’s announcement in August that Lynparza added to Avastin maintenance met the primary endpoint of PFS in first-line advanced-stage ovarian cancer, irrespective of BRCA status.1

The combination of Lynparza and Avastin maintenance reduced the risk of disease progression or death by 41% in the overall trial population. The PAOLA-1 trial also identified the patient population with greater clinical benefit from the addition of Lynparza to Avastin maintenance: patients with a BRCA mutation and homologous recombination deficiency (HRD).

The PFS of these patients was more pronounced, reaching 37.2 months in both patient populations, with hazard ratios (HR) of 0.31 for BRCA-mutated and 0.33 for HRD-positive. However, in the HRD-negative/unknown subgroup of patients, the improvement in PFS was not substantial (16.9 months in Lynparza arm vs 16 months in placebo arm) with an HR of 0.92.2

PRIMA trial: Zejula maintenance significantly improves PFS in newly diagnosed advanced ovarian cancer

Similar to the PAOLA-1 trial, the PRIMA trial enrolled newly diagnosed advanced ovarian cancer patients, regardless of their BRCA status.

Zejula maintenance met the primary endpoint (PFS) of the PRIMA trial, by demonstrating a significant improvement in PFS compared to placebo (13.8 vs 8.2 months, respectively) in the overall population. The patient population with a more pronounced benefit was the HRD-positive subgroup, which showed a mPFS of 21.9 months compared to 10.4 months with placebo.

Notably, Zejula maintenance also demonstrated a significant reduction (of 32%) in the risk of disease progression or death in a patient subgroup called “HRD-proficient” (HRD-negative).3,4 Thus, Zejula maintenance demonstrated a substantial PFS benefit in all newly diagnosed advanced ovarian cancer patients.

How will these results impact the management of ovarian cancer disease?

  • New standards of care in ovarian cancer: Based on the impressive data shown in the PAOLA-1and PRIMA trial, the combination of Lynparza and Avastin maintenance, and Zejula maintenance, will become new standards of care for newly diagnosed advanced ovarian cancer. Both therapies are expected to gain a strong uptake in the ovarian cancer market.
  • Offering treatment beyond BRCA mutations: Zejula showed a statistically and clinically meaningful improvement in PFS in all newly diagnosed advanced ovarian cancer patients, so physicians would not have to screen for BRCA mutations or HRD status. This could give Zejula an advantage in the market over Lynparza monotherapy, as the latter is approved for only BRCA-mutated patients in the first-line setting.
  • Personalised treatment in ovarian cancer: Both Zejula and the combination of Lynparza and Avastin showed a bigger improvement in PFS in HRD-positive patients compared to the overall population. These results lead to the question of whether physicians can deliver HRD testing in the clinic. Currently, this biomarker is not commonly tested in practice because of the lack of a reliable test to evaluate patient’s HRD status. Development and implementation of reliable HRD tests will therefore be crucial to determine which treatment is most suitable for newly diagnosed ovarian cancer patients.
  • More clarity on treatment of HRD-positive patients: Lynparza in addition to Avastin did not show a significant improvement in PFS in HRD-negative patients. As a result, we expect the combination to be limited to approximately 50% advanced ovarian cancer cases, which represent the HRD-positive patients. Another limitation for the use of this combination will be its safety profile. Even though there was no significant difference in the quality of life between treatment arms in the PAOLA-1 trial, the combination of Lynparza plus Avastin showed more treatment interruptions, reductions, and discontinuations than Avastin alone. Thus, fragile patients who are not fit enough to cope with this combination may be ineligible for this treatment.

VELIA trial: Veliparib also shows a substantial PFS improvement in newly diagnosed advanced ovarian cancer, but can it compete with the other PARP inhibitors?

AbbVie’s drug development strategy for veliparib stands out compared with that of other companies developing PARP inhibitors in ovarian cancer. The VELIA trial is the only trial evaluating a PARP inhibitor in combination with chemotherapy, followed by PARP inhibitor maintenance treatment for first-line setting.

The mPFS in the overall population was of 23.5 months in the induction and maintenance veliparib arm, compared to 17.3 months in the placebo arm. This benefit was more pronounced in patients with a BRCA mutation (mPFS: 34.7 vs 22.0 months for veliparib and placebo, respectively).5

The VELIA trial, however, received several criticisms after the presentation of the results. One of the main critiques is the lack of an arm evaluating chemotherapy in combination to placebo, followed by veliparib maintenance, as it makes it unclear if the addition of veliparib to chemotherapy is needed to obtain the observed benefit.

Other critiques discussed the increased toxicity with the veliparib addition to chemotherapy and the lack of benefit over what it has been reported in other first-line trials evaluating PARP inhibitors.6 Therefore, we do not expect a strong uptake of veliparib if it receives a marketing authorisation for the treatment of newly diagnosed advanced ovarian cancer based on the VELIA trial.

As PARP inhibitors approvals and label expansions ramp up across multiple markets in the coming years, drug developers should explore strategic considerations such as:

  • What drug classes will be the key competitors of PARP inhibitors?
  • What will likely limit PARP inhibitors’ uptake?
  • What’s the potential reimbursement for PARP inhibitor monotherapies or for combination therapies containing PARP inhibitors?
  • What clinical data physicians need to make treatment decisions?

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  1. AstraZeneca press release. “Lynparza Phase III PAOLA-1 trial met primary endpoint as 1st-line maintenance treatment with bevacizumab for advanced ovarian cancer”. August 14, 2019.
  2. Ray-Coquard IL, et al. Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Annals of Oncology. 2019; 30 (suppl_5): v851-v934.
  3. González Martín A, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Annals of Oncology. 2019; 30 (suppl_5): v851-v934.
  4. GlaxoSmithKline press release. “Phase 3 PRIMA trial of Zejula® (niraparib) is the first study to show a PARP inhibitor significantly improves PFS, regardless of biomarker status, when given as monotherapy in women with first-line platinum responsive advanced ovarian cancer”. September 28, 2019.
  5. Coleman RL, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. [published online September 28, 2019] doi: 10.1056/NEJMoa1909707.
  6. OncLive article. “Frontline Veliparib Shows Intriguing PFS Findings in VELIA Trial”. September 28, 2019.