This article is a Clarivate Analytics Market Insight report, an ongoing series featuring expert reviews of hot topics in the pharma/biotech field, with analysis and discussion on the factors currently affecting the industry.
Poly ADP-ribose polymerase (PARP) inhibitors have created much excitement in the medical community since the demonstration in 2005 of the extreme sensitivity of BRCA-mutant (BRCAm) xenografts to PARP inhibition, and they have now revolutionized ovarian cancer treatment with significantly reduced risk of disease progression.
AstraZeneca’s first-to-market Lynparza entered in the U.S. for fourth-line germline BRCAm (gBRCAm) advanced ovarian cancer in December 2014 and saw quick uptake in the 10% to 15% target population. Since then, competition has intensified rapidly, with Clovis Oncology’s Rubraca launched in December 2016 and TESARO’s Zejula launched in April 2017, followed by an extension of Lynparza’s label in August 2017. Other PARP inhibitors are also in development, including AbbVie’s veliparib and Pfizer’s talazoparib, and indeed use of this class of drugs is not likely to be limited to ovarian cancer, with positive late-stage data for Lynparza also seen in breast cancer.
Cortellis Consensus Forecast data (source Thomson Reuters I/B/E/S) predict sales of the PARP inhibitor class to increase from $218 million in 2016 (Lynparza only) to $3.712 billion in 2021, rising further to ~$5 billion in 2023; both Lynparza and Zejula are forecast to be blockbusters by 2021 and Rubraca should join them by 2023.
|NAME||GENERIC NAME||DEVELOPER||MARKET ENTRY||2017 FORECAST (US $ MILLION)||2021 FORECAST (US $ MILLION)|
|Rubraca||Rucaparib||Clovis Oncology||December 2016||58||663|
Approximately 22,000 women in the U.S. are diagnosed with ovarian cancer each year and it is the fifth leading cause of cancer death. The majority of ovarian malignancies are epithelial in origin and 10% to 15% harbor BRCAm. There is a high unmet need, with 70% to 80% of all ovarian cancer patients diagnosed with advanced disease and a five-year survival rate of ~ 50%. While platinum-based chemotherapy is the current standard of care in the first line, it is estimated that 60% to 65% of all patients with ovarian cancer could benefit from an effective maintenance therapy following recurrence. Roche’s injectable VEGF inhibitor Avastin was approved in the U.S. in platinum-sensitive recurrent ovarian cancer in December 2016 which will intensify competition, but it is the oral PARP inhibitors that are transforming the ovarian cancer treatment landscape.
PARP inhibitors in ovarian cancer
PARP inhibitors were designed to target BRCAm tumors and exploit a concept called synthetic lethality, which occurs when the simultaneous perturbation of two genes results in the loss of viability while perturbation of either gene alone renders the cell still viable. BRCA genes are involved in repairing damaged DNA and mutations in BRCA are associated with a high risk of developing certain cancers. PARP is a protein most notably involved in DNA repair and apoptosis. Since BRCAm cells have increased reliance on PARP to repair DNA, simultaneous inhibition of DNA repair by PARP inhibitors should result in loss of cancer cell viability and have a significant benefit in patients with BRCAm.
Lynparza was the world’s first PARP inhibitor to enter the market following accelerated U.S. approval and launch in December 2014 for use in the fourth line in patients with gBRCAm platinum-sensitive advanced ovarian cancer. Accelerated approval was based on data from a phase II study showing an overall response rate of 34%, median duration of response of 7.9 months and median progression-free survival (PFS) of 6.7 months.
The second approved PARP inhibitor Rubraca was granted accelerated approval by the FDA in December 2016 for third-line germline and/or somatic BRCAm (g/sBRCAm) advanced ovarian cancer based on an objective response rate of 54% and median duration of response of 9.2 months in two single-arm phase II trials (Study 10 and ARIEL-2).
While the FDA had only granted fourth-line approval for Lynparza in December 2014, the EMA had at that time approved Lynparza for earlier maintenance therapy for recurrent g/sBRCAm ovarian cancer. However, it is Zejula that became the first FDA-approved PARP inhibitor for second-line ovarian cancer maintenance treatment in March 2017, and importantly, this approval was regardless of BRCAm status, increasing the target population to 70% and giving Zejula an edge over Lynparza. In the NOVA study in the ovarian cancer maintenance setting, Zejula reduced the risk of disease progression/death by 73% and improved median PFS by 21 versus 5.5 months for placebo in patients with BRCAm but also improved median PFS by 9.3 versus 3.9 months in patients without BRCAm for a 55% reduction in risk.
In this highly dynamic and competitive market, Zejula’s advantage in the second-line maintenance setting was not long-lived since in August 2017 Lynparza was also approved for second-line maintenance treatment based on the SOLO-2 study and Study 19. The phase III SOLO-2 trial confirmed the benefit of Lynparza in gBRCAm patients, demonstrating a 70% reduced risk of disease progression/death and an independent central review evaluation showing an impressive improvement in PFS of 24.7 months (30.2 versus 5.5 months for placebo). In patients of any BRCA status, Lynparza reduced the risk of disease progression/death by 65% and improved PFS by 8.4 versus 4.8 months, according to phase II Study 19.
Clovis is also seeking approval for Rubraca for second-line maintenance use. In June 2017, data from the ARIEL3 trial were reported which showed a median PFS of 10.8 months for all patients, irrespective of tumor genetics, compared with 5.4 months for placebo; in patients with BRCAm, median PFS was 16.6 versus 5.4 months. Rubraca filings in this setting are expected in the short term.
This heightened competition in ovarian cancer could soon also extend to the first-line setting, with various monotherapy and/or combination studies in BRCAm and/or non-mutated patients planned or ongoing for Lynparza (SOLO-1, PAOLO-1), Zejula (PRIMA), Rubraca (MITO-25) as well as veliparib (VELIA). The first to receive approval is expected to be Lynparza, with data from the SOLO-1 study in first-line BRCAm advanced ovarian cancer expected later in 2017 and filings in 2018.
Market dynamics of PARP inhibitors
Having enjoyed a monopoly in the recurrent platinum-sensitive ovarian cancer setting for two years, Lynparza is the current market-leading PARP inhibitor worldwide, and also to date the only PARP inhibitor approved outside the U.S. Second-to-market Rubraca’s earlier-line treatment positioning and broader label (third-line, g/sBRCAm) gave it a competitive advantage over Lynparza (fourth-line, gBRCAm). However, approval of third-to-market Zejula in broader second-line ovarian cancer maintenance changed the U.S. PARP landscape with Zejula becoming the most prescribed PARP inhibitor in the U.S. within three months of its launch. Zejula is also the only once-daily PARP inhibitor while both Lynparza and Rubraca require twice-daily dosing. At the time of writing, 2017 sales for Lynparza, Rubraca and Zejula are forecast at $296 million, $58 million and $70 million, respectively, rising to $1.067 billion, $667.0 million and $1.642 billion, respectively, in 2021; Rubraca is predicted to achieve >$1 billion sales by 2023.
Lynparza’s August 2017 approval in the second-line maintenance ovarian cancer setting is likely to challenge Zejula and the status quo, and with Rubraca’s strong ARIEL3 data, it is expected to add to the competition in this setting. The toxicity profiles are relatively similar for all PARP inhibitors, with hematological and gastrointestinal side effects and fatigue the most common, but the drugs overall being well tolerated. First-line ovarian cancer data are awaited as are further late-stage data from other PARP inhibitors, particularly veliparib and talazoparib, which will give greater clarity on how the market will play out in future. Additionally, PARP inhibitors are being explored in other settings and Lynparza recently showed the first positive late-stage data for a PARP inhibitor outside ovarian cancer with improved PFS over standard of care seen in BRCAm breast cancer. Approval in other malignancies will further intensify competition among the PARP inhibitors.
The PARP inhibitors are a relatively new class of drugs that have already significantly affected ovarian cancer treatment. Numerous trials as monotherapy, in combination and in other malignancies are ongoing. Strong first data in settings outside ovarian cancer, notably in BRCAm breast cancer, hint at future approvals in other indications. The market for PARP inhibitors is highly competitive, and the battle for leadership among the already approved PARP inhibitors Lynparza, Rubraca and Zejula is far from over. With their novel mechanism, good efficacy and safety, all PARP inhibitors could play important roles in improving patient’s lives and will likely be a commercial success.