Mar 02, 2016
Attendees of the 2016 Genitourinary Cancers Symposium raised a number of provocative questions after General Session 2: Potential Targets for Advanced Prostate Cancer. Many of the questions pertained to two presentations about the influence of DNA repair alterations on the risk of developing prostate cancer and the response to prostate cancer therapy. Ros A. Eeles, MD, PhD, FRCP, FRCR, FMedSci, and Johann S. De Bono, MD, MSc, PhD, FRCP, FMedSci, MB ChB—both of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust—each gave one of these presentations.
Session Co-Chair Karen E. Knudsen, PhD, of the Sidney Kimmel Cancer Center at Thomas Jefferson University, provided in-depth answers to some of the questions raised during the session and to other unanswered questions from the Symposium.
Q: The presentation from Dr. De Bono focused on initial results from the phase II TOPARP trial that is evaluating the effects of olaparib, a PARP inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) who have been heavily pretreated with androgen receptor-directed therapies and one to two prior lines of chemotherapy. Of the 49 evaluable patients, 33% attained an objective response to olaparib. Notably, responses were enriched in patients with alterations in a number of DNA repair genes, including BRCA1/2, ATM, and Fanconi’s anemia genes. What does the future hold for olaparib?
Dr. Knudsen: Three weeks after the Genitourinary Cancers Symposium, on January 28, 2016, the U.S. Food and Drug Administration granted a breakthrough therapy designation for olaparib on the basis of positive initial findings from the TOPARP study. This designation applies to single-agent treatment of BRCA1/2- or ATM-mutated mCRPC in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent (i.e., abiraterone or enzalutamide).
Q: Do we know which patients are most likely to respond to a PARP inhibitor? Is it only patients who have BRCA1/2 or ATM mutations?
Dr. Knudsen: The initial TOPARP work focused on identifying the genomic alterations that sensitize mCRPC to PARP inhibition. Although patients identified as having BRCA1/2 or ATM mutations responded favorably to PARP inhibition, other patients who did not have those mutations also responded, which suggests that the benefits of this class of therapy extend beyond those isolated mutations. Identifying other predictive biomarkers and mutations is an active area of investigation right now, and more data are needed to effectively determine which patients will respond to olaparib.
In addition, we do not yet understand how certain mutations in DNA repair pathways affect DNA repair. I do not think we can take all DNA repair mutations and classify them in one bucket. We are going to have to determine which are detrimental to the tumor, which are disease-promoting, and which may lead to a good therapeutic option.
The field is at the tip of the iceberg right now according to our understanding of just BRCA1/2 and ATM.
Q: Do we know when somatic BRCA mutations develop during the course of prostate cancer? Do these mutations occur early on, or are they acquired in later stages of disease, upon treatment?
Dr. Knudsen: That is a great question and an important issue for the field to address. We know that some patients have germline BRCA mutations, whereas others develop somatic BRCA mutations. We will need to conduct longitudinal testing to determine when in the disease course somatic mutations develop. We do know that patients with localized prostate cancer have a low reported rate of DNA repair abnormalities, which increases to about one-third of the patients with castration-resistant prostate cancer.
Q: Given the data suggesting that BRCA mutations confer a predisposition to prostate cancer, along with the data indicating that BRCA mutations sensitize patients with prostate cancer to PARP inhibition, should clinicians be testing patients for BRCA mutations? If so, when?
Dr. Knudsen: There are no current guidelines to indicate when patients with prostate cancer should be tested for BRCA mutations or whether we should be screening individuals without disease for such mutations. However, there are three specific groups of patients for whom testing makes sense. The first group comprises patients with disease that progresses on hormone therapy and standard of care. It would be useful to know whether these patients harbor a BRCA mutation that might lend itself to PARP inhibitor therapy. In addition, the field may want to consider genetic testing for two other groups of patients: those with a family history of prostate cancer or BRCA-related cancers (e.g., breast, ovarian, and pancreatic) and patients who present with early disease (i.e., before age 50).
One of the difficulties in making recommendations about routine testing is that different countries have different capacities for genetic testing. In the United States, it is almost becoming routine at major centers to immediately perform a genetic panel on patients with prostate cancer who experience progression during hormone therapy to identify somatic mutations, and BRCA is included in the panel. However, this capability may not hold true outside the United States.
Q: In tumors with DNA repair defects, is there a rationale for combining PARP inhibitors with radiation?
Dr. Knudsen: Yes, there is strong biological rationale for combining a PARP inhibitor with radiation, because this sensitizes tumor cells to the DNA-damaging effects of radiation that then are unrepaired because of PARP inhibition. I am aware of at least one study that is about to start that will combine a PARP inhibitor with radiation (radium-223) for men with CRPC with bone metastases that have progressed on AR directed therapy or chemotherapy.
Q: Should oncologists aggressively treat patients with prostate cancer who have a known BRCA1/2 or ATM mutation—for example, patients with low- or intermediate-risk prostate cancer?
Dr. Knudsen: That is a tough question to answer right now. At my institution, we would certainly follow a patient like this carefully. However, whether we would change the patient’s course of therapy on the basis of what we currently know is uncertain.
Given this very new knowledge of DNA repair alterations and their influence in prostate cancer, there certainly are a number of questions that we will want to address. Do we change first-line therapy for patients with a known BRCA or ATM alteration? Do we think differently about patients with localized disease who would traditionally receive surgery or radiation; do we change their therapies as well? We do not know the answers to those questions. When we have a better handle on screening, the frequency of DNA repair alterations, and the disease course for patients with these alterations, we will better be able to make predictions about prognosis and treatment outcomes.
Q: How are the findings about the influence of DNA repair alterations on prostate cancer treatment likely to change the field?
Dr. Knudsen: A new day is dawning in prostate cancer, given some of the findings that have come to light during the past couple of years. First, we have determined that PARP inhibitors function remarkably well in a subset of patients. Second, data have revealed that DNA repair alterations are enriched in advanced disease. We had not fully appreciated that before. Third, we now know that testosterone promotes DNA repair. This helps explain why hormone therapy and radiation work so well together in locally advanced disease.
Moving forward, all of these factors need to be taken into account to define the next wave of therapeutic strategies that target DNA repair pathways.