Nearly a quarter of men with metastatic castration-resistant prostate cancer have genomic alterations that map to currently available treatment options that have been found to improve outcomes for patients with those specific actionable targets. The challenges of how to test more men with these types of prostate cancers and how to incorporate the results of those tests into treatment decision-making is the topic of a recent Oncology Grand Rounds paper published in the Journal of Clinical Oncology by Catherine H. Marshall, MD, MPH, Assistant Professor of Oncology at the Johns Hopkins University School of Medicine (2023; doi: 10.1200/JCO.23.00350). Research is ongoing to improve rates of cascade testing (informing and then testing family members of known genetic mutation carriers) for men who may be BRCA1/2 mutation carriers (and, therefore, at higher risk for prostate cancer and its aggressive types)-and then to better understand how to provide screening and potentially early treatment for those with mutations, explained Alexandra Sokolova, MD, Assistant Professor of Medicine at Oregon Health & Science University. Research is also ongoing to better understand if patients with certain mutations would benefit more than current standard of care from other drug combinations. "There is still a lot to be learned," Sokolova told Oncology Times, who previously collaborated with Marshall on research projects.
1 What stood out to you from this paper?
"PARP inhibitors are important tools we now have available for prostate cancer patients. I think there is still a lot to be learned: which is the right patient population that can benefit from PARP inhibitors?
"Research has caused some dialogue in the genitourinary oncology field, especially when it comes to patients with HRR-negative mutations. Current data suggest benefit in the HRR-positive patient population, particularly in patients with BRCA mutations. For the HRR-positive cohort, it's important to understand in which scenarios are appropriate to use: PARP monotherapy or PARP inhibitors plus abiraterone.
"I agree with Dr. Marshall that, in BRCA1/2 mutation carriers, good performance status and prior treatment with ADT or ADT plus docetaxel as first line would be a good combination to consider a patient for treatment with abiraterone plus PARP inhibitors. But so far, PARP inhibitors are only approved for patients with BRCA1 or BRCA2 mutations. And that's still where we see the biggest benefit from the PARP inhibitor.
"We don't currently have data about PARP inhibitor and abiraterone combination use in first-line metastatic castration-resistant prostate cancer after progression on an androgen receptor pathway inhibitor (ARPI) in the past. I agree it currently should not be used in this scenario due to the lack of data. However, there is some data suggesting that continuing ARPI pathway inhibitor with chemotherapy after progressing on one-enzalutamide with docetaxel-improved outcomes. It is possible in the future it will be worthwhile to look into the combination (PARP inhibitor + ARPI) after the APRI pathway inhibitor, and I would be curious to see what the data would show. Potentially, there would be a biological role for that in the future. But, currently, this is a data-free zone and I would not use it now clinically outside of clinical trials."
2 The research noted genetic mutation status for patients with prostate cancer can help aid treatment decision-making. What are the barriers to this?
"I think the biggest barrier to incorporating genetic information into decision-making is not having genetic information on time. We need to do more testing, and we need to do it early and in a timely manner to be impactful. I think we're doing much better than we used to. But I think there is still room for improvement. Educating patients, educating providers, improving access to both germline and somatic testing, and limiting the financial impact they have on patients are all important.
"The other important point, especially if we talk about germline mutations, is early identification and potentially decreasing risk of metastatic prostate cancer with cascade testing. Whenever we have a patient with a germline mutation, it's very important to initiate cascade testing and test both their female and male family members. This way we would be able to identify those patients before they develop prostate cancer.
"We know that BRCA1/2 is associated with a high chance of breast and ovarian cancer, but it's also associated with a higher risk of developing and more aggressive prostate cancer phenotype. That means that, if we're able to catch those patients before they develop prostate cancer and monitor them closely and treat them at the early signs of prostate cancer development, hopefully we can prevent the development of lethal prostate cancer. I think cascade testing is the best way to do that."
3 Do patients struggle to undergo testing because of cost, lack of providers, lack of getting the right referral, or other factors?
"I think all of the above. Traditional models for germline testing include referrals to genetic counselors, and there is a shortage of genetic counselors nationwide. So the wait time can make it hard to get in. Also, not all insurance covers a genetic counseling visit or germline testing. Some commercial platforms offer patient-initiated germline testing for a generally smaller out-of-pocket fee (perhaps a few hundred dollars) and no insurance is involved. But undergoing that still involves getting to the provider and paying for the test.
"It also involves educating the providers. Medical oncologists are very busy during appointments with our patients, and because patients often come to us with more acute issues, it's not always on the top of our list to talk about genetic testing. So having a workflow where we're reminded to talk about both somatic and germline genetic testing is important."