Leonard G. Gomella, MD
Genetic testing for germline mutations within the DNA repair pathway, although not standard of care, is becoming more widespread in prostate cancer, helping to define optimal screening protocols for those at greater risk and potential treatment strategies for patients, according to Leonard G. Gomella, MD.
“It's very important that men who have aggressive forms of prostate cancer, metastatic prostate cancer, or a very strong history of related cancers such as hereditary breast, ovarian, pancreatic, and melanoma consider germline genetic testing because it may impact a variety of aspects of their care,” said Gomella. “We don't have too much information yet on early screening, but that is starting to come into vogue if a patient has a strong family history. Certainly, for more advanced cases of disease, knowing a patient’s germline genetic testing status is very important because that may be very critical in directing how they are cared for in the future.”
In an interview with OncLive
during New York GU: 13th Annual
Interdisciplinary Prostate Cancer Congress®
and other Genitourinary Malignancies, Gomella, professor, chair, Department of Urology, and director, Sidney Kimmel Cancer Center Network, Thomas Jefferson University Hospital, discussed the state of genetic testing in prostate cancer, shared his recommendations for screening, and provided perspective on where the field is headed.
OncLive: The field of prostate cancer continues to move at a rapid pace. What have been some of the most important updates in terms of genetic testing?
: In various settings, genetic testing is becoming more broadly applied to help us understand a patient’s risk for prostate cancer. We recognize the fact that the majority of men still have sporadic prostate cancer; there’s no clear signal to indicate they have a family history or require genetic testing.
Genetic testing has really evolved over the past 5 or 6 years in prostate cancer. Everyone knows that the government sponsored the major Human Genome Project that was completed in the early 2000s. At that time, many companies became involved with genetic testing. In 2013, 2 major occurrences took place. One of them was Angelina Jolie, bringing to the world the concept of what an inherited gene might be for cancer risk. In her case, it was the BRCA1/2
gene with breast and ovarian cancer. Additionally, the United States Supreme Court decreed that you could not patent a naturally occurring normal or mutated gene. That really led to a rapid expansion in the number of commercial entities that were interested in doing genetic testing.
We're very far behind in prostate cancer compared with breast and ovarian cancer, but we're starting to catch up in this area. We’ve been able to successfully identify that similar genes in the DNA repair pathway that increase the risk of ovarian and breast cancer in females also appear to be involved in the same pathway in men with prostate cancer. That has been the big breakthrough in the past 2 or 3 years: the identification of very similar genetic abnormalities and [applying this knowledge] to [improve] the care of men with prostate cancer.
The FDA granted a priority review designation to rucaparib (Rubraca) in metastatic castration-resistant prostate cancer (mCRPC) and olaparib (Lynparza) in homologous recombination repair-mutant mCRPC. Do you expect these approvals to prompt more widespread use of genetic testing?
Right now, in the field of urology, urologic oncology, and prostate cancer, we don't have a pharmacogenomic-approved drug. We anticipate that the PARP inhibitors that are under priority review right now will certainly increase the interest in genetic testing among providers who treat men with all stages of prostate cancer. Certainly, this is going to be a big breakthrough. Once we have pharmacogenomic coupling of the approval for use of the drug, it's going to increase the interest in the whole world of genetic testing in prostate cancer.
What are your recommendations for screening men for prostate cancer?
Right now, if a man knows that he has a BRCA1/2
mutation or one of the other commonly mutated DNA repair pathway genes, we recommend that they have a conversation about screening for prostate cancer—perhaps a little earlier than they might otherwise screen.
Now, how do men come to that point? Right now, we're not doing widespread genetic testing for prostate cancer, but men who have a strong family history of hereditary breast and ovarian cancer in female relatives, and those who have a strong history of advanced prostate cancer in their male relatives, may want to consider germline genetic testing. [Genetic testing is] in the screening recommendations, but it is certainly not a standard of care. The National Comprehensive Cancer Network guidelines recommend that if patients have a family history and a BRCA1/2
mutation, they may want to consider starting screening for prostate cancer earlier in the course of a normal lifespan.
In terms of androgen receptor inhibitors, enzalutamide (Xtandi) was recently approved by the FDA for use in the castration-sensitive setting. How are the earlier use of these agents impacting sequencing strategies?
We've seen the use of these drugs shift [over the years], and now we're at the point where we're using them for [patients with] nonmetastatic CRPC. We have darolutamide (Nubeqa), enzalutamide, and [apalutamide (Erleada)] for use in patients who have a rising prostate-specific antigen (PSA) but have no evidence of lesions on any imaging study. We're using these agents at that point. Additionally, some early research is evaluating the use of these agents earlier on, as a potential way to [treat] earlier stages of prostate cancer, and in a neoadjuvant setting for high-risk disease, but we're certainly not there yet. At this point, in nonmetastatic CRPC, these agents have received FDA approval and many of us consider them to be a standard of care, particularly in men who have rapid PSA-doubling times and are at risk of developing early metastatic disease.
Could you discuss some exciting data that were presented at the 2020 Genitourinary Cancers Symposium?
We got some good information about the potential use of some of these newer agents in the neoadjuvant setting. The entire area of using these next-generation androgen biosynthesis pathway inhibitors and immunotherapies earlier in the course of the treatment before the patient develops metastatic disease is garnering a lot of attention. We don't have any completed trials yet; however, in our regulatory approval process, we always move drugs back earlier and earlier in the course of disease. This is all being examined extensively. We've looked at neoadjuvant chemotherapy and the results are a little bit mixed; they're not as promising as we thought, but it could be that some of the newer agents that are used for advanced disease may have more of a role.
What is the important take-home message from advances in prostate cancer?
Genetic testing is still in an early phase in prostate cancer, but it has an increasing role. One of the challenges is that we didn't really have enough genetic counselors to help us with the large number of men who may benefit from genetic testing, but we are working on alternative approaches. We have some initiatives. For example, at the Sidney Kimmel Cancer Center, where we're working on training programs, we're developing an app to help medical oncologists and urologists potentially screen patients for genetic testing.
Additionally, screening for prostate cancer still remains highly controversial. We're getting better at identifying the men who are going to derive the most benefit from screening, but the primary care doctors really don't have a standard of care for prostate cancer screening. While they may adapt some guidelines and recommendations, there is no standard of care for prostate cancer screening today. That remains a major challenge. We’re all working toward developing the proper approaches and protocols to identify the men who are going to derive the most benefit from screening for prostate cancer.
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