Introduction from Clearity's Scientific Director, Dr. Deborah Zajchowski
In our third newsletter of this clinical trial series, we focus on a treatment modality that is called "maintenance" therapy and is sometimes used by advanced stage cancer patients to prevent or delay the return of cancer or to keep existing tumor burden stable. In their articles, Drs. Evan Friend and Cory Bentley describe clinical situations for the use of such therapy, the specific experience with taxanes, and new phase III clinical trials that ask whether an exciting class of drugs called PARP inhibitors will be effective as maintenance treatment in women whose cancer has recurred.
The importance of checking the eligibility criteria for clinical trial entry soon after diagnosis is underscored by these clinical trials. In addition to being a recurrent cancer patient who has responded to platinum, there are characteristics of your tumor blueprint that may also be important for enrollment. As described in more detail in the article below, the knowledge that you are a BRCA (gene linked to hereditary breast and ovarian cancer) patient or that your tumor has a mutation in the BRCA1 or BRCA2 genes or other genes important for repairing DNA damage may impact your response to these drugs as well as your ability to enroll in these trials.
To assist in the identification of these and other clinical trials, we have created a search engine that allows you to find open clinical trials suited for your tumor blueprint (search using a drug-molecular-target) or for a drug you are interested in (search using the drug name).
Maintenance Therapy for Ovarian Cancer
by Evan Friend, MD
The concept of maintenance therapy is based on the idea that by continuing treatment, patients will delay the time to subsequent recurrence or progression of the disease. Whether or not this therapy will lead to improved long-term survival is a question that has yet to be answered and multiple clinical trials are in progress to address this.
The decision to pursue ongoing or "maintenance" therapy for a woman achieving an ovarian cancer remission is certainly not clear-cut and therefore, can be a difficult one. The majority of women with ovarian cancer are able to achieve remission after the completion of front-line chemotherapy following successful primary surgery for resection of the tumor. It is not unusual, however, for women to have mixed emotions at the time of completion of chemotherapy. On the one hand, there is a sense of relief in making it to the "finish line," but on the other hand, a patient may feel anxious due to the fact that treatment is no longer taking place.
Thus, one may be fearful that the tumor burden is not 100% gone, or that cancer may recur without ongoing chemotherapy. This is where maintenance therapy may be appropriate. Maintenance chemotherapy can involve the continuation of one of the same agents utilized in the initial treatment, such as paclitaxel (Taxol). Given as a maintenance treatment, this chemotherapy drug is usually given less often or at a lower overall cumulative dose for a period of several months and possibly as long as one year. To date there has been no single trial which clearly demonstrates significant long-term survival benefits for maintenance Taxol, although a 2010 meta-analysis (Hess L et al Cancer 116:5251-60) that evaluated the pooled results from multiple trials suggested that women with advanced stage ovarian cancer may benefit. Results from ongoing clinical trials should address the value and appropriate dosing schedule for maintenance Taxol (e.g., GOG-212).
Drugs used as maintenance therapy can also be different from those that have induced remission or resulted in stable disease. For example, the PARP inhibitor, olaparib, and the angiogenesis inhibitor, pazopanib, have recently been tested in this setting. Increased time to disease progression was observed with each of these drugs in early trials and phase III trials will determine whether there will also be an overall survival advantage for women who take these drugs as maintenance therapies. (See our accompanying article on the PARP inhibitors). In addition to increasing overall survival, any regimen involving continuation of therapy to "maintain" the response or stable disease state also aims to maximize the patient's overall quality-of-life for as long a time as possible, while clearly recognizing that continuation of treatment may have a negative impact. This may be related to adverse side effects, such as peripheral neuropathy and intermittent low white blood cell counts with increased susceptibility to infections as well as the time and effort required for the patient participating in an ongoing long-term therapy program involving intravenous chemotherapy.
Anticipating that the role of maintenance therapy will be ultimately proven in the setting of a randomized clinical trial, the next critical issue will be to identify the type of maintenance intervention able to prevent cancer recurrence, while avoiding toxicity and preserving quality of life. We expect that the selection of this maintenance therapy will be informed by the patient's tumor molecular profile.
Eligibility Criteria in Clinical Trials:
Clearity first reported on drugs inhibiting PARP (Poly-ADP ribose polymerase), an important enzyme for tumor cell proliferation and survival, in its September 2010 patient newsletter. At that time, PARP inhibitors were just entering clinical trials and only two trials were recruiting patients. Now, thanks to promising results from the early
trials, multiple PARP inhibitors are moving forward in ovarian cancer clinical trials and are also being evaluated in other cancer types. PARP inhibitors have proven most effective in patients with a mutation in one of the BRCA genes (click here for a BRCA overview), but tumors with mutations in other DNA repair pathways may also be sensitive to PARP inhibition. A quick search of Clearity's clinical trial search engine for ovarian cancer trials using "PARP1/2" as the search term in the targeted drug field pulls up 20 clinical trials. Most are phase I studies but there will soon be new phase II and even phase III trials added.
In fact, four companies have indicated that they are moving PARP inhibitors into pivotal phase III trials for ovarian cancer soon, including Abbott, AstraZeneca, Clovis, and Tesaro. All of these trials will evaluate the efficacy of these inhibitors as a maintenance therapy. As described in the accompanying article, maintenance therapy is given to patients that have responded to their previous treatment with the aim of prolonging their time to recurrence or progression. For Abbott's veliparib, the phase III study will be in newly diagnosed patients with stage 1C-IV high grade serous cancer in combination with platinum/paclitaxel with randomization to the maintenance therapy with either veliparib or placebo. For the other three PARP inhibitor trials, the maintenance therapy is for women whose cancer recurred and responded again to platinum-based treatment.
Tesaro's President, Mary Lynn Hedley, PhD talked with Clearity about the phase III trial for niraparib. The niraparib trial will have many study sites across North America. Patients will be randomized into the study drug group or placebo group 2:1, meaning that for every three patients that enroll, two will get the study drug and one will get the placebo. Dr. Hedley explains that this 2:1 design study will take longer to complete because more patients are necessary for the trial, but she knows that it is important to patients that they have a good chance to be on the study drug. The niraparib trial will take patients regardless of their BRCA mutation status because some studies indicate that patients with high grade serous ovarian cancer can have mutations other than BRCA in DNA repair pathways that make them equally susceptible to PARP inhibitors.
AstraZeneca's PARP inhibitor, olaparib, will be tested in phase III studies this year, but will specifically focus on patients who have BRCA mutations, based on good responses in those patients in their phase II studies. According to the updated analysis for their phase II maintenance therapy study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) on June 2, women with BRCA mutations (germline or tumor) had a significantly improved time to tumor progression: 11.3 months on olaparib vs. 4.3 months on placebo.
Clovis is also planning to start a phase III trial this year with its PARP inhibitor, rucaparib, for platinum-sensitive high grade serous ovarian cancer. This trial will have a similar design to the one described for niraparib, but will additionally stratify patients based on BRCA status as well as evidence for other biomarkers associated with DNA repair defects.
It is clear that all of these phase III trials are paying close attention to patients' tumor blueprint either to decide on enrollment or to help further identify which patients are most likely to respond to the respective drugs.
Apart from a patient's tumor molecular profile or blueprint, many other factors determine patient eligibility, including the number and types of prior chemotherapies and other treatments, stage of disease, and health factors. For this reason, it is imperative that patients consider clinical trials early in their treatment, so that they do not inadvertently make themselves ineligible for participation in promising trials. Patients and their doctors have to be one step ahead of their cancers as they map out possible treatment paths. Clearity can help by using each patient's own blueprint to identify possible options that include both approved treatments and clinical trials. A number of Clearity's patients have participated in PARP inhibitor trials. Read about the experience of one of these women here.
The current and upcoming PARP inhibitor trials hold the promise of new treatment options for ovarian cancer patients. These studies will also bring a wealth of new data that will help guide future patients and their doctors to make informed treatment choices.
Mutations in the BRCA1 or BRCA2 genes (pronounced BRACK-uh) confer a high risk of developing breast and ovarian cancer. These genes encode proteins that are guardians of the genome, playing an important role in DNA repair. If one of the BRCA genes is disabled by a mutation, the cells without BRCA function are not able to correct mistakes (mutations) that occur when cells divide or when they are exposed to environmental stresses that cause damage to DNA as part of their normal experience. The BRCA mutant cells therefore accumulate many mutations, some of which trigger the development of cancer.
A mutated BRCA gene can be inherited from a parent, as was the case recently publicized for actress Angelina Jolie. A mutation inherited from a parent is called a germline mutation. The mutation will be present in every cell in the body so a simple test using DNA found in the blood will be able to evaluate if there is a mutation. Sometimes, a BRCA mutation can occur sporadically as part of tumor development, a somatic mutation. This type of mutation is found only in the tumor cells and not in the rest of the cells of the body so somatic mutations can only be detected using cells obtained from the tumor, such as through biopsy.
BRCA was recently in the center of a drama that unfolded in the Supreme Court. The Supreme Court ruled that some components of diagnostic company Myriad Genetics' patent claims on the BRCA genes were invalid. This ruling changes the landscape for BRCA testing and will ultimately allow patients and clinicians less expensive access to BRCA mutation tests.
BRCA mutational status is an important part of a tumor blueprint that can be used to determine the best possible treatment options. In early clinical trials, tumors with BRCA mutations have been shown to be more responsive to a class of drugs called PARP inhibitors.
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Dr. Cory Bentley, firstname.lastname@example.org.
The information included in this newsletter is for educational purposes only. It is not intended nor implied that this information be a substitute for professional medical advice. You should always consult your healthcare provider to determine the appropriateness of the information for your own situation.