Biopharmaceutical Report I
PARP inhibitors like Tesaro’s (NASDAQ:TSRO) niraparib, Clovis Oncology’s (NASDAQ:CLVS) rucaparib and AstraZeneca’s (LON:AZN) approved Lynparza (olaparib) will find it tough to differentiate from one another, experts said.
Since they are thought to have comparable efficacies, the type and nature of side effects may be the main distinction, they noted. The side effect profiles, however, are not yet showing much separation, they said.
And while niraparib and rucaparib may have the upper hand compared to Lynparza since the former two are being studied in a broader population, Tesaro’s and Clovis’ biomarker strategy somewhat similar to each other, experts add.
Lynparza is approved only for patients who carry a germline BRCA mutation, while niraparib is being studied in a larger group of patients who have homologous recombination deficient (HRD) tumors and are said to constitute around 40-60% of all ovarian cancer patients, experts added. Rucaparib is relying on an approach that considers sensitivity based on an loss of heterozygosity (LOH) score derived from genome wide LOH driven by HRD mutations. This is said to include over 65% of patients who have either BRCA mutations or are classified as BRCA-like, according to a Society of Gynecologic Oncology 2015 presentation.
Lynparza received an FDA nod on 19 December 2014 for patients who have received at least three lines of chemotherapy based on subset efficacy data from a single-arm, open label Phase II study. The EMA approval in the maintenance setting was based on the overall Phase II trial, which the FDA’s Oncologic Drugs Advisory Committee had voted against.
Lynparza is being studied in the maintenance setting for patients following first-line platinum therapy and platinum-treated relapsed patients with BRCA mutations in Phase III SOLO1 and SOLO2 trials, respectively.
While maintenance setting data from Tesaro’s NOVA Phase III trial are expected in 4Q15, Clovis plans to release Phase III Ariel3 results in 1H16.
Side-effect profile may be separator since efficacy is comparable
The side-effect profiles may have a role in differentiating one PARP from another, said Dr Brian Slomovitz, division director, Gynecologic Oncology University of Miami Health System. While there’s no major comparable difference right now between the different PARP inhibitors, they might stand out eventually once the drugs have been in use for long, he added.
In niraparib’s Phase I trial, the only completed clinical study, Grade 4 thrombocytopenia was a dose-limiting toxicity for ovarian cancer patients at 400 mg QD, while other side effects across other indications included Grade 1-2 fatigue, anorexia, nausea and myelosuppression. The Phase III trial is evaluating niraparib at a 300 mg QD dose.
In the 204-patient Phase II Ariel2 trial with rucaparib, 11% had elevated AST/ALT (aspartate transaminase/alanine transaminase), 19% patients had anemia or decreased hemoglobin and 15% of patients experienced fatigue among Grade 3-4 adverse events, according to a European Society for Clinical Oncology 2015 presentation.
Based on adverse event (AE) reports evaluated by the FDA for Lynparza, 0.8% (21/2618) of patients reported having myelodysplastic syndrome/ acute myeloid leukemia versus 1.3% (2/160) of those on placebo, according to an FDA Advisory committee document.
From the data it would seem like there’s less genomic toxicity with the rucaparib, since myelodysplasia has not been observed, said Penson.
It is not clear which PARP inhibitor has more bone marrow toxicity than others, but while other side effects like Grade 1-2 nausea, fatigue or elevation of liver enzymes would be considered manageable, myelodysplasia is something that is being closely watched for, particularly in the maintenance setting, said Dr Alan D’Andrea, Alvan T. and Viola D. Fuller American Cancer Society professor of Radiation Oncology, Harvard Medical School, Boston. Oncologists have learned to manage side effects like nausea and other gastro-intestinal (GI) related effects, said Dr Emmanouil Saloustros, attending physician, General Hospital of Heraklion “Venizelio-Pananio”, Greece.
Price Reduction similar to Europe anticipated
In the maintenance setting, PARP inhibitors are generally well tolerated and relatively easy to give, said Dr Richard Edmondson, chair, Gynecological Oncology, Faculty Institute for Cancer Sciences, University of Manchester, UK, based on available data.
Myelosuppression fears remain, other toxicities largely manageable
The side-effect profiles for niraparib, rucaparib and Lynparza are quite similar barring a few factors like liver enzyme elevations that was seen with rucaparib, said Penson. Transient elevation of liver enzymes is generally tolerable, noted D’Andrea, adding side effects like leukemia would be considered as bad toxicities.
If there is no OS survival advantage, it is important to at least offer an improvement in QOL, said Saloustrous.
While myelodysplasia has been seen in some adjuvant studies, in generally PARP inhibitors are well tolerated, agreed Saloustrous. The important issue with using a PARP as maintenance therapy is that it does not negatively impact subsequent treatments, added Edmondson.
The risk of secondary malignancies is also a major one, said Saloustrous. This news service reported on May 4 that physicians highlighted the risks for PARP-inhibitor treatment to possibly lead to resistance to platinum-based therapies and secondary malignancies.
Companion diagnostic, differences in HRD companion diagnostic still unclear
The understanding that BRCA mutations are not necessary or sufficient for sensitivity to PARP inhibitors was an important one, said D’Andrea. While Lynparza’s approval is for gBRCA patients, Tesaro is working with Myriad Genetics (NASDAQ:MYGN) to utilize its myChoice HRD diagnostic to identify patients with HRD mutations, according to a 20 November 2014 release. Comparatively, Clovis is in collaboration with Foundation Medicine (NASDAQ:FMI) aimed at identifying LOH.
Clovis’ strategy has generated interest among physicians, this publication reported on 12 May.
HRD is a fairly binomial phenomenon, so a test would be also be binary, said Edmondson. Using HRD, though, is not unique anymore, said Slomovitz. Within the laboratory environment, the different companion diagnostics in development do appear to have fairly similar characteristics and it is expected to translate into the clinical setting as well, he added.
There’s no clear idea of which approach is better, said D’Andrea. The best test would be a multiplex test that is a combination of looking at the BRCA gene, the HRD test and other DNA repair genes, he noted. Taking multiple factors into account will improve the predictive power of any test, he added.
Manasi Vaidya has a Masters degree in biotechnology. After a stint in a research lab, she spent two years as correspondent in India for BioSpectrum, a publication focused on the Asian biotechnology industry. She then moved to the United States to pursue a Masters degree in Science, Health and Environmental Reporting at New York University. Manasi has reported primarily on topics that combine health and policy, and her work has appeared in Nature Medicine, Nautilus and Scienceline. Her coverage at BioPharm Insight focuses on cancer.