Therapy focus – Ovarian cancer field readies for phase III readouts
Ovarian cancer specialists are in for a lively few months, with a run of pivotal trial readouts, two or more filings and the outcome of an EU submission for a long-forgotten project – events that could collectively move the field forward.
Any such development will be welcome as ovarian cancer remains a difficult-to-treat disease that has seen little progress in recent years (see table below). Moreover, it has so far not been much of a target for immuno-oncology, which has taken great strides in other indications.
Some progress was made with the late 2014 conditional approval of a targeted agent, AstraZeneca’s Lynparza, but the mainstay of treatment remains surgery followed by platinum and taxane chemotherapy. Nevertheless, a review of the field reveals a full phase III pipeline, with 11 different agents being examined in a total of 15 studies, and a further six agents in or entering registration-directed phase II or II/III trials.
Moving towards approval
Four of the phase III agents are PARP inhibitors, namely Lynparza, Tesaro’s niraparib, Clovis’s rucaparib and AbbVie’s veliparib. The first three are being studied as maintenance therapies in BRCA-mutant patients, an approach thought to take best advantage of PARP inhibition's role in DNA repair. AbbVie, though, is conducting a larger study of veliparib in combination with first-line chemo, enrolling both wild-type and BRCA-mutant patients.
AstraZeneca's Solo-2 trial should read out this quarter, but some analysts believe that data are more likely later in the year. If this is the case, Tesaro’s Nova trial will probably be the first of the PARP studies to report. This evaluates three different subpopulations based on patients’ mutation status, and effectively has three opportunities to achieve a positive result (Therapy Focus – PARP inhibitor class set to come of age in 2016, March 1, 2016).
Tesaro also expects data from its Quadra phase II trial in fourth-line ovarian cancer around the same time as Nova reports, and believes the combined data sets would support an NDA submission planned for the second half.
Lynparza somewhat controversially gained early US approval – despite a negative advisory committee vote – for third/fourth-line use based on a subgroup analysis of gBRCA mutant patients. This highlighted the fact that regulators, perhaps mindful of the relative lack of new agents in ovarian cancer, were keen to give physicians new therapies.
Back from the dead
One surprise is that AstraZeneca’s almost forgotten anti-VEGF tyrosine kinase inhibitor cediranib – which was pretty much consigned to history with a phase III failure in colorectal cancer in 2012 – is in fact under EMA review for ovarian cancer. The project was quietly filed in July 2015 based on phase II data and thus must now be approaching a decision.
AstraZeneca is seeking approval as a monotherapy in Europe, although cediranib is being developed in combination with Lynparza in the third-line setting in an NCI-sponsored phase II/III study, Cocos.
In the shorter term, AstraZeneca could face competition to Lynparza in 2017 from Clovis, which is expected to start a rolling NDA for its PARP inhibitor rucaparib in the second quarter. This will be for platinum-sensitive, relapsed, BRCA-mutant disease, based on the phase II Ariel-2 study in the fourth-line setting.
Clovis is also conducting Ariel-3 in third-line treatment, which is expected to complete enrolment in the next few months and render results around a year later.
|Lynparza||AstraZeneca||>2L maintenance, gBRCA mutant||NCT01874353||Feb 2016|
|Niraparib||Tesaro||3L maintenance, pt-sensitive, gBRCA mutant||NCT01847274||Q2 2016|
|Perjeta||Roche||<3L recurrent pt-resistant, low HER3 mRNA expression||NCT01684878||Apr 2016|
|Lynparza||AstraZeneca||1L maintenance, gBRCA mutant||NCT01844986||Jul 2016|
|Rucaparib||Clovis||>3L maintenance, pt-sensitive||NCT01968213||Q2 2017|
|binimetinib||Array||2-4L, low grade serous||NCT01849874||H2 2017|
|Lynparza||AstraZeneca||3L relapsed gBRCA mut||NCT02282020||Dec 2017|
|Vigil Ovarian||Gradalis||1L maintennance||NCT02346747||Dec 2017|
|Niraparib||Tesaro||1L maintenance, pt-sensitive, HRD-positive||NCT02655016||Mar 2018|
|Avelumab||Pfizer||<3L, pt-resistant /refractory||NCT02580058||Mar 2018|
|Yondelis||J&J/Pharmamar||3L, BRCA mutant||NCT01846611||Sep 2018|
|Lurbinectedin||Pharmamar||<4L, pt resistant||NCT02421588||Oct 2018|
|Veliparib||Abbvie||1L maintenance||NCT02470585||Jan 2019|
|Lynparza||AstraZeneca||>3L maintennance pt-sensitive, relapsed, sBRCA or HRR mutant||NCT02392676||Jun 2019|
|Yondelis||Pharmamar/J&J||<3L, partial pt sensitive||NCT01379989||Dec 2019|
|Cediranib/Lynparza||AstraZeneca||<3L, recurrent pt-resistant or refractory||NCT02502266||N/A|
|Farletuzumab||Eisai||Low CA125, pt sensitive||NCT02289950||Nov 2017|
|AZD1775||AstraZeneca||Pt-resistant TP53-mutated||NCT02272790||Jul 2017|
|Mirvetuximab soravtansine||Immunogen||Folate receptor alpha positive||NCT02631876||Mar 2018|
|Vargatef||Boehringer Ingelheim||>3L||NCT01610869||Oct 2017|
Regulators have been prepared to accept PFS as a primary endpoint in ovarian cancer, and indeed most of the pivotal phase III studies use this. An exception is Pfizer/Merck KGaA’s Javelin Ovarian 200 study of the PD-L1 inhibitor avelumab. This is one of only two immuno-oncology approaches in the disease, the other being Gradalis’s personalised cancer vaccine Vigil.
Ovarian is the fifth-most common cancer affecting women and has a 46% five-year survival rate. Other than achieving earlier diagnosis, there has been relatively little improvement in chemo in recent years, so it will be welcome indeed if some positive data emerge in 2016.