Therapy focus – PARP inhibitor class set to come of age in 2016
The PARP inhibitor class has made a remarkable comeback from the nadir it reached when Sanofi’s iniparib failed in separate phase III trials for triple-negative breast and non-small cell lung cancers. That recovery was catalysed largely by a single event: the late 2014 conditional approval of AstraZeneca’s Lynparza, a project that had itself been discontinued but was later resurrected with a post-hoc analysis of phase II data.
Thus, despite the class having been almost written off by many, PARP inhibitors have recovered strongly with five agents now in a total of 18 phase III studies. Moreover, six of these phase III trials are due to render results this year, an analysis by EP Vantage shows (see table below).
AstraZeneca is likely to be the first to report data with progression-free survival results from its Solo-2 study of Lynparza due imminently. This study is designed to show a benefit as maintenance therapy in third-line, relapsed BRCA mutant ovarian cancer.
This is close to the drug’s current indication, which is for the treatment of germline BRCA (gBRCA) mutant ovarian cancer patients in the salvage setting – fourth line or later – where a 34% response rate had been seen in a 137-patient study and led to an accelerated approval.
If positive, Solo-2 should support a move to full approval, although Lynparza’s label in ovarian cancer may also be expanded on the basis of the Solo-1 study in first-line gBRCA disease, which renders results a few months later.
Two phase III studies with Lynparza in other cancer indications, namely the Gold study in second-line gastric cancer and the Olympiad study in adjuvant treatment of gBRCA mutant breast cancer, are also expected to read out in the first half of this year.
Another study that renders results in the April to June timeframe is Tesaro’s Nova phase III trial of niraparib in third-line ovarian cancer. This has a complex design that recruited two cohorts based on gBRCA mutant status. The gBRCA mutants will be evaluated first, and results will no doubt compared to Lynparza’s in Solo-2.
The study also examines a subgroup of gBRCA wild types with homologous recombination deficiency (HRD) and then a third group of all non-gBRCA mutants in a hierarchical fashion. This effectively gives Nova three opportunities to render a positive result.
Tesaro expects data from its Quadra phase II trial in fourth-line ovarian cancer around the same time, and with Nova, this is expected to support an NDA submission in the second half. Tesaro is also conducting phase III trials in gBRCA mutant breast cancer, called Bravo, and first-line maintenance ovarian cancer, called Prima.
A phase III study with AbbVie’s veliparib in neo-adjuvant early stage triple negative breast cancer – which does not select on the basis of BRCA mutation status – and the Embraca trial with Medivation’s talazoparib in metastatic breast cancer, are also due to report results this year. AbbVie has four other phase III studies underway with veliparib, studiously avoiding ovarian cancer and pursuing other solid tumours.
Clovis is potentially further down the regulatory track than its one phase III study with rucaparib suggests, as it holds breakthrough therapy designation for tumour BRCA-mutated ovarian cancer in patients who had had two prior platinum-containing regimens. Pending results from the phase II Ariel-2 trial, Clovis plans to submit an NDA for the treatment of fourth-line or later ovarian cancer with either BRCA mutations or the “BRCAness” signature.
The breakthrough therapy designation was based on Study 10 and data from part 1 of ARIEL2. Study 10 included 17 patients with relapsed, platinum-sensitive gBRCA ovarian cancer, and showed a response in 12/17 (71%). The ARIEL2 data showed a response in 15/23 (65%) of ovarian cancer patients with BRCA mutations.
|PARP inhibitors: Phase III studies|
|Solo-2||BRCA mut ovarian, >2L||297||placebo||NCT01874353||Feb-16|
|Gold||2L gastric cancer||500||paclitaxel +/-||NCT01924533||Apr-16|
|Olympiad||gBRCA1/2 mut mBC||310||physicians choice||NCT02000622||May-16|
|Solo-1||BRCA mut ovarian, 1L||397||placebo||NCT01844986||Jul-16|
|Polo||gBRCA mut pancreatic cancer, first line maintennance||145||placebo||NCT02184195||Oct-17|
|Solo-3||Relapsed gBRCA mut ovarian cancer, 3L||411||Single agent chemotherapy||NCT02282020||Dec-17|
|-||Pt-sensitive, relapsed ovarian cancer, sBRCA or HRR mutant, maintennance Tx||167||placebo||NCT02392676||Jun-19|
|OlympiA||mBC, gBRCA1/2 mutations||1500||placebo||NCT02032823||Mar-20|
|Nova||Maintenance Tx, 3L pt-sensitive, gBRCAmut ovarian cancer||490||placebo||NCT01847274||Q2/16|
|Bravo||HER2 negative, gBRCA mut breast cancer||306||physician's choice||NCT01905592||Sep-17|
|Prima||Maintenance Tx, HRD-positive ovarian cancer, response to front-line Pt chemo||305||placebo||NCT02655016||Mar-18|
|neoadjuvant, early stage TNBC||624||carboplatin +/- veliparib vs chemo||NCT02032277||Apr-16|
|HER2-negative, BRCA-associated breast cancer||270||carbotax +/-||NCT02163694||Jan-17|
|Tx-naïve, squamous NSCLC||975||carbotax +/-||NCT02106546||Apr-17|
|1L, non-squamous NSCLC, current or former smokers||525||carbotax + veliparib vs physicians choice||NCT02264990||Nov-17|
|Continuation maintenance Tx, ovarian cancer||1100||carbotax +/-||NCT02470585||Jan-19|
|Embraca||mBC with gBRCA mutation||429||vs physician's choice||NCT01945775||Jun-16|
|Ariel-3||Switch maintenance Tx, Pt-sensitive ovarian cancer||540||placebo||NCT01968213||Q2-17|
PARP (poly ADP-ribose polymerase) inhibitors are designed to disable the tumour cell’s ability to repair damaged DNA, leading to synthetic lethality, without affecting normal cells. In most cases, the strategy has been to exploit the fact that BRCA1/2-mutated cells have DNA repair mechanisms that are already impaired.
EvaluatePharma consensus data suggest the sell-side believes 2020 sales of niraparib will be $660m, followed by around $600m for Lynparza and velirapib and $220m for rucaparib, respectively. However, it’s a fair bet that these figures are not additive. BRCA mutation prevalence in most cancers is very low, suggesting there may only be a small commercial opportunity for PARP inhibitors unless studies show effectiveness in non-BRCA populations. This may take some time yet.