October 2019, Volume XXXIII, No 7
Prostate Cancer Research
A promising new class of drugs
rostate cancer kills 30,000 men in the United States every year. Of those patients, many live with the disease for five to 15 years prior to dying from it. Others live to their normal life expectancy while receiving treatment for advanced prostate cancer, and then die of other causes.
Until recently, the number of deaths per year was declining, but we are seeing a recent increase in the number of prostate cancer-related deaths per year. The reason is unclear and likely multifactorial. Clinicians are concerned about the possible rise in the number of patients presenting with metastatic disease, potentially as a result of a decline in routine prostate-specific antigen (PSA) screening of healthy men.
Most men diagnosed with prostate cancer have a curable form of the disease that can be treated with radiation or surgery, which then leads to their disease being eliminated. Even with optimal initial therapy, up to 20% to 30% of patients will experience a relapse after surgery or radiation. Of those patients, most will be treated with and respond well to hormonal therapy (treatments intended to reduce the stimulation of testosterone on the tumor). Because of the effectiveness of hormonal approaches, many men will be able to live to a normal life expectancy without facing the life-threatening form of the disease, but a substantial proportion of those treated with hormonal therapy will develop a resistant, and lethal, form of the disease.
Any patient with newly diagnosed metastatic disease should be offered genetic testing.
Death from prostate cancer comes from the confluence of two events. The first is “castration resistance,” or worsening of the disease despite treatments that lowered the level of testosterone. The second is from metastasis. Some patients develop castration-resistant prostate cancer without metastasis—however, they live with a high risk of the eventual formation of metastatic tumors in the bone, lymph nodes, or organs.
Genetic and molecular drivers
New research on the genetics of prostate cancer is revealing that as the disease progresses into castration-resistant prostate cancer (CRPC), multiple different genetic and molecular drivers lead to heterogeneous disease outcomes. Among these drivers is the recent recognition of the role of alterations of the cellular processes involved in the repair of damaged DNA.
Recent studies have shown that upwards of 25% of patients with advanced prostate cancer harbor some mutations or alterations in the genome that lead to impaired DNA repair. This includes mutations in the critically important BRCA2 gene. The BRCA genes (BRCA1 and BRCA2) play important roles in preventing cancer from forming by repairing the damage done to the DNA in our cells on a daily basis (through inflammation, ultraviolet radiation, and other processes). If the BRCA2 gene is lost or mutated, minor mutations do not get repaired and get propagated, leading to the risk of cancer. It may also render existing cancer to be resistant to conventional treatments.
One of the positive consequences of the mutation is that tumors may be sensitive to a new class of drugs called poly-ADP ribose polymerase (PARP) inhibitors. PARP is an enzyme in cells that helps repair DNA when it is damaged. PARP inhibitors are used as a cancer treatment in hopes of blocking the PARP from repairing the damaged DNA, causing the cancer cells to die—a process called “synthetic lethality” (as the cancer cell tries to replicate, or synthesize, its DNA, the cell dies because it cannot make repairs). Several PARP inhibitors are in clinical development in a variety of clinical settings.
At the University of Minnesota, we are one of the leading sites for the TRITON3 study, which is a phase 3 registration study that is enrolling patients with BRCA1, BRCA2, and ataxia telangiectasia mutated (ATM) alterations. These patients are required to have already been treated with the standard of care androgen receptor-targeted therapies. We are also participating in the TRITON2 study, which is already showing promising results that have been presented at international meetings. The drug being studied in the two TRITON studies is rucaparib, and it has achieved breakthrough designation status from the U.S. Food and Drug Administration (FDA).
Additionally, Arpit Rao, MD, in the Department of Medicine, Division of Hematology, Oncology and Transplantation at the University of Minnesota Medical School, is developing a phase 3 study that will test rucaparib in combination with enzalutamide in patients who do not have altered DNA repair in the form of the mutation. The basis for this study is the observation that the androgen receptor itself may contribute to DNA repair. We hypothesize that inhibiting the androgen receptor with enzalutamide, an FDA-approved standard care of therapy, will lead to temporary loss of DNA repair function in the tumor cell. Therefore, we think that co-targeting the tumor with a PARP inhibitor and an androgen receptor inhibitor may lead to beneficial results compared to targeting the androgen receptor alone. In fact, this paradigm has also already shown some preliminary efficacy in a study done in the United Kingdom with abiraterone and olaparib, a different PARP inhibitor.
This leads to a consideration of how and when we would test prostate cancer for an alteration in DNA repair. As we begin to understand the importance of these agents in patients with altered DNA repair, the guidelines are evolving toward recommending earlier testing for involved patients. Now, any patient with newly diagnosed metastatic disease should be offered genetic testing.
Genetic testing for these DNA-impaired genes comes in the form of either germline testing (testing family genetics) or somatic testing (testing the genetics in the tumor itself). Germline genetic testing is very easy and can be done with a cheek swab. We recommend that patients who undergo testing have their results interpreted with a genetic counselor. Genetic counselors can help other family members get tested to see if it was passed down, and can help guide the patient’s management.
This paradigm has also already shown some preliminary efficacy.
It is important to consider that not all prostate cancer patients with BRCA mutations in their tumor will have familial BRCA2 alterations, but most patients who have prostate cancer and who have a BRCA2 alteration will have it in their tumor as well. If the BRCA mutation is found in all of the prostate cancer patient’s normal cells, the gene is hereditary, and it can continue to get passed down to his children.
In addition to increasing the risk of prostate cancer, BRCA mutations are known to increase the risk of breast cancer, ovarian cancer, and pancreatic cancer. Women who are found to be carriers of the BRCA2 mutation need to seriously consider these risks, as these cancers can be prevented. Catching cancer early is crucial. There is no good screening test for ovarian cancer, so by the time ovarian cancer becomes detectable, it may have already spread to other parts of the body. There is fairly convincing data that women carriers should undergo an ovariectomy as well as a prophylactic mastectomy. It has been shown that by doing that, those women are less likely to die of breast and ovarian cancer.
Men that inherit the BRCA2 alteration are at an increased risk for prostate cancer. Men with the inherited mutation who already have developed localized prostate cancer have a higher risk of recurrence of the disease after surgery or radiation therapy. Preventative removal of the prostate is not an option, but being aware of the alteration is still advantageous as it allows one to monitor the situation. Closer surveillance would hopefully result in earlier detection of the tumor.
Early data from the TRITON2 study is showing promising results for patients with metastatic castration-resistant prostate cancer. Results from this study could lead to not only more possible treatment options but also more effective treatment options.
Researchers are optimistic that an understanding of DNA repair, the BRCA gene, and its impact on the risk of lethal cancer among men can lead to an improvement in outcomes. From an oncology perspective, it represents one of many new developments. We are understanding that the molecular basis for the cancer’s progression is leading to changes in treatment that can benefit patients. We’re getting a deeper understanding of the molecular heterogeneity of prostate cancer. That understanding is altering our ability to offer effective treatments for patients.
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