Vaccines and PARP inhibitors are among the promising emerging therapies.
A growing understanding of ovarian cancer is spurring the development of new therapeutics and diagnostics that also apply to other types of cancer. Therefore, despite a small incidence rate (22,240 this year, according to the American Association for Cancer Research) and a small market, ovarian cancer is experiencing an uptick in interest.
“During the past 40 years, nothing has been introduced that has dramatically affected overall survival,” Marc Mansour, Ph.D., COO, Immunovaccine, said. Instead, most research has involved optimizing known drugs and regimens.
“We gained a better understanding of the mechanisms of ovarian cancer, though, so that ovarian cancer has become a good scientific indication for a variety of therapies,” Dr. Mansour said. Although ovarian cancer has an orphan designation, there is ready access to the tumor tissue for every patient treated, he explained. “There is a big need, but only limited options.”
Improved understanding reveals a direct link among T cells, the immune system, and patient longevity. “It is interesting as an immunogenic cancer, and there is great interest in testing that. Histologically, when you see a lot of CD8 T cells inside the tumor, it means the patient has a robust immune system that can fight the cancer,” Dr. Mansour explained.
Decision Resource predicts the drug market for ovarian cancer therapeutics in the seven major markets (the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan) will more than triple during the next decade, growing from $460 million in 2011 to $1.4 billion in 2021. Another report, this time from BCC, anticipates a 13.1% CAGR between 2013 and 2018 for all ovarian cancer diagnostics and therapeutics, including surgeries. Using those broad parameters, it estimates the 2021 market at $34.6 billion, slightly more than twice 2012 levels.
Immunovaccine plans a Phase II trial using its depot technology DPX-Survivac in combination with low-dose oral cyclophosphamide as an immune modulator. Dr. Mansour said the 250-patient trial will look at progression-free survival and is slated to begin the first half of 2014. Results from the Phase I trial elicited “one of the strongest responses we’ve seen in the literature.” Some patients exhibited an average stimulation factor 350 times higher than baseline responses, and one patient showed a stimulation factor 850 times greater than baseline.
In Phase I, DPX-Survivac was administered thrice. “You need to kickstart the immune system and give a booster shot every few months to maintain it,” he added.
DPX-Survivac appears to elicit a cytotoxic T-cell immune response against cells with survivin peptides on HLA class I molecules. Therefore, it teaches the immune system to recognize survivin, a tumor-associated antigen present in many types of cancer, including brain, breast, colon, and melanomas. “What’s particularly interesting,” Dr. Mansour continued, “is when cancer vaccines like ours are applicable to other cancers. A trial for gliomas is slated for early 2014.”
In September, Northwest Biotherapeutics activated the second site for a DCVax-Direct Phase I/II trial. The M.D. Anderson Cancer Centers in Houston and Orlando are performing the trial for solid, inoperable tumors, including ovarian, lung, colon, pancreatic, liver melanoma, head and neck, and other cancers. Results are expected by year’s end. DCVax activates dendritic cells, which are injected directly into the tumors to shrink their sizes.
Researchers also are testing checkpoint inhibitors—mAbs targeting PD-1 and CTLA4, for example—that enhance T-cell response. Different checkpoint regulators seem to be present on different types of cancers and within different patient populations. Therefore, identifying multiple immune checkpoints may enhance treatment effectiveness for large populations.
In September, Compugen released early-stage data for CGEN-15049, a novel immune checkpoint protein. CGEN-15049 is expressed on many cancers and inhibits the immune response of many immune cells. In vitro studies show it inhibits natural killer cells and modulates regulatory T cells. Therefore, mAb therapeutics look promising in blocking immune inhibition. CGEN-15049 is expressed in ovarian, lung, breast, colorectal, gastric, prostate, and liver cancers.
Compugen has discovered a total of nine immune checkpoints. It is developing therapeutic antibodies against these candidates, and “is moving toward preclinical testing of those antibodies in relevant in vitro and in vivo model systems,” Anat Cohen-Dayag, Ph.D., president and CEO, said.
In August, Compugen announced mAb development and commercialization collaborations for two of them—CGEN-15001T and CGEN-15022. As Dr. Cohen-Dayag said, “CGEN-15001T demonstrated expression in various other solid cancers and hematological malignancies, and CGEN-15022 is expressed in numerous types of epithelial cancers, including ovarian cancers.”
Also in September, AstraZeneca licensed Merck’s oral small molecule inhibitor of WEE1 kinase. Known as MK-1775, this cell-cycle checkpoint regulator is in Phase IIa clinical trials in combination with standard-of-care therapies for patients with p53-deficiant ovarian cancer. The regulator causes certain tumor cells to divide without DNA repair, killing them. Phase I research suggests that MK-1775 will be particularly effective with DNA-damaging chemotherapy agents.
“The compound has demonstrated encouraging clinical efficacy data, and we intend to study it in a range of cancer types where there is a high unmet medical need,” Susan Galbraith, Ph.D., head of AstraZeneca’s oncology innovative medicines unit, said in a statement.
Among emerging therapies, “Poly ADP-ribose polymerase (PARP) inhibitors look promising,” Hillary Theakston, executive director, The Clearity Foundation, said.
That outlook is based on significant tumor shrinkage in early clinical trials involving patients who have undergone multiple therapies. “Seeing high responses in late-stage patients is very interesting,” Mary Lynne Hedley, Ph.D., president and CSO, Tesaro, added.
Tesaro launched a Phase III PARP inhibitor trial in summer 2013 with the European Network of Gynecological Oncological Trial Groups (ENGOT). More than a dozen countries are involved in the two-arm study. The inhibitor, niraparib, is being tested as a maintenance therapeutic in patients with high-grade serous, platinum-sensitive, relapsed ovarian cancer among patients with germline BRCA mutations, and in another patient group lacking the BRCA mutation. In earlier trials, “The median number of days they maintain responses is greater than 400,” Dr. Hedley explained.
“Clinical data suggests that patients with platinum-sensitive, high-grade serous ovarian cancer are very sensitive to niraparib and that those with the germline BRCA mutation may respond a little better,” Dr. Hedley noted. At the optimal dose of 300 mg, a 75% RECIST (response evaluation criteria in solid tumors) rate was achieved. For all dose levels, the RECIST rate was 46% in the same patient population.
In September, AstraZeneca enrolled the first patient in its Phase III trial of olaparib for BRCA-mutated ovarian cancer. The trial is designed to determine progression-free survival when olaparib is used as a maintenance monotherapy after platinum-based chemotherapy. Because the BRCA1 and BRCA2 tumor suppressors are linked to hereditary breast and ovarian cancer, there is the potential that olaparib may apply to both cancers.
Clovis Oncology also launched a Phase II study during the summer. It studies rucaparib in patients with gBRCA mutations in ovarian cancer. Phase I results showed an 89% clinical benefit rate across all doses. Evidence suggests genetic analysis can help identify patients who benefit from PARP inhibitor therapy.
As a more advanced field of research, angiogenesis inhibitors will account for 60% of the ovarian cancer therapeutic market by 2021, according to Decision Resources. Avastin® by Roche/Genentech/Chugai and trebananib by Amgen were cited as leading contenders.
Amgen’s trebananib is in Phase III trials. This investigational peptibody—a hybrid peptide/antibody platform—is designed to inhibit the angiopoietin axis and, therefore, the growth of new blood vessels that feed the tumor. Angiopoietins are also involved in the formation of new lymphatic vessels.
Endocyte is targeting a vinca chemotherapy to cancer cells by linking it to folate. “The folate receptor is expressed on many cancer cells, but not on most normal cells,” Theakston explained. “About 80–90% of ovarian tumors express high levels of the folate receptor.
“Endocyte has completed single-arm studies of vintafolide (EC145) in patients with advanced ovarian cancer. Vintafolide (EC145) has also been evaluated in the Precedent study, a randomized Phase II trial comparing vintafolide (EC145) with Doxil® to Doxil alone in women with platinum-resistant ovarian cancer. While this study has completed enrollment, a Phase III study named Proceed, also in women with platinum-resistant ovarian cancer, is now accruing patients.”
Endocyte also uses a folate-targeted molecular imaging agent (Etarfolatide) to non-invasively identify tumors that overexpress folate receptors and, hence, may be more likely to benefit from vintafolide.
“Technologies that are standard of care for other cancers aren’t routinely applied to ovarian cancer,” Theakston said. “Advanced tests that allow genomic characterization of a tumor aren’t generally used because ovarian cancer is very heterogeneous molecularly, with alterations that occur throughout the genome. Therefore, it’s not a simple matter of testing for alterations in one or two genes or for levels of a hormone receptor and matching results to treatments.”
New diagnostics are vital. “In the future, whole-gene sequencing, RNA sequencing, and proteomic analysis also will be helpful in characterizing tumors, and measuring circulating tumor cells in the blood is a promising approach to detect disease progression early and to monitor disease in real time,” Theakston noted. “These technologies can help us understand which drugs may work for which patients by identifying the pathways activated in her cancer.”