Therapeutic Focus - Disappointment a recurring theme in ovarian cancer pipeline

Analysis

AstraZeneca’s decision to shelve olaparib in ovarian cancer is the latest in a string of frustrations for researchers in this difficult condition. Diagnosed most often after the cancer has spread, fewer than half of all women will survive for five years, making new medicines an urgent need for patients and clinicians (see table below).

Surgery followed by chemotherapy remains the primary treatment protocol, demonstrating the absence of novel treatments for ovarian cancer; recent research shows that many women develop a resistance to platinum-based cytotoxics. However, a considerable late-stage pipeline suggests the potential for a breakthrough from a novel drug class in the near future – Roche’s versatile but chequered antibody Avastin is due a final European decision very soon (Avastin in ovarian gets EU backing but US will be harder won, September 26, 2011).

Difficult diagnosis

The sixth-leading cause of cancer death among women, ovarian cancer treatment is complicated by the late stage at which it is usually diagnosed. Acording to the US National Cancer Institute (NCI), 62% of women are diagnosed at stage III, after the cancer has metastasised to distant sites, making it all the more difficult to treat.

The five year survival rate in those stage III patients is just 27%. Across all stages the five-year survival rate is 44%, well below breast cancer’s 89%, for example. According to US government and cancer registry data published in June in the journal Cancer, five-year survival rate has improved only eight percentage points in a 31-year period beginning in 1975.

It is not for lack of trying with novel treatments. Since the last time EP Vantage looked at the field, three phase III candidates have failed – EPO906, abagovomab and phenoxodiol, with the latter now in early stage tests as an IV medication instead of as an oral treatment (Therapeutic focus - Novartis announces ovarian failure as Asco approaches, May 27, 2010). In addition, Johnson & Johnson earlier this year scrapped US plans to market the EU-approved Yondelis after the FDA demanded another trial.

Hope

There is some hope on the horizon. Early next year, GlaxoSmithKline is expected to report phase III data on Votrient, already approved and marketed for renal cell carcinoma. The 900-patient test pits the multi-kinase inhibitor against placebo in stage II, III and IV ovarian, fallopian tube or primary peritoneal cancer that has not progressed following chemotherapy.

Antibodies make an appearance in the form of Eisai’s MORAb-003 (farletuzumab), a product of the Japanese company’s acquisition of Morphotek for $325m in 2007. It remains active in a 1,080-patient phase III trial in combination with chemotherapy in women with platinum-resistant disease. That trial is expected to report late next year.

However, in a demonstration of how difficult the disease is, a second pivotal trial in combination with paclitaxel in patients with platinum-resistant disease was terminated earlier this month when an independent data monitoring committee determined that it was unlikely to meet statistical significance.

AstraZeneca still has a late-stage hope in the form of AZD0530, another tyrosine kinase inhibitor (TKI). Its phase II/III trial in ovarian cancer, being conducted in collaboration with Cancer Research UK and University College London, is a test in 102 patients in combination with platinum resistant cancer; a readout is not expected until 2013.

Another drug in an investigator-led trial is Cell Therapeutics’ drug conjugate Opaxio, based on paclitaxel. The Gynecologic Oncology Group and NCI are trialling it in a 1,100 patient programme in stage III and IV disease. Earlier this year the company reported that an interim survival analysis is expected in the second half of 2011, which will be triggered when 30% of the patients in the control arm have died.

Boehringer-Ingelheim reported that its Lume-Ovar 1 trial of the TKI Vargatef, also known as BIBF 1120, completed recruitment of 1,300 patients in July. That trial in stage IIB-IV ovarian cancer patients is in combination with chemotherapy and as a maintenance therapy. With 41-month progression free survival as the main endpoint, that trial may not read out for several years, however.

In phase II and earlier a wider variety of treatment approaches are being tried, including antibodies, oncolytic viruses, vaccines and PARP inhibitors. Should these latest shots on goal miss their targets, the hope must be for greater accuracy from the candidates that follow. 

Phase III ovarian cancer pipeline
Product Company Generic name Pharmacological class
Votrient GlaxoSmithKline pazopanib hydrochloride Multi-kinase inhibitor
AZD0530 AstraZeneca saracatinib Src tyrosine kinase inhibitor
MORAb-003 Eisai farletuzumab Anti-a-folate MAb
Opaxio Cell Therapeutics/Novartis paclitaxel poliglumex Taxane
Karenitecin BioNumerik Pharmaceuticals cositecan Topoisomerase I inhibitor
AMG 386 Amgen trebananib Angiopoietin receptor antagonist
Vargatef Boehringer Ingelheim nintedanib Tyrosine kinase inhibitor

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