Increased Genetic Screening May Lead to Earlier Prostate Cancer Diagnoses

William L. Dahut, MD

Improved screening modalities for patients with a known genetic predisposition to developing prostate cancer may lead to increased and earlier identification of prostate cancer, said William L. Dahut, MD.

As such, an ongoing study led by the National Cancer Institute (NCI)¹ aims to follow the prostate health of 500 men with known germline alterations that put them at a higher risk of developing prostate cancer, explained Dahut.

Patients enrolled will have MRIs every 2 years, he continued. Additionally, patients will undergo prostate-specific antigen (PSA) testing, and investigators will also determine prostate cancer treatment, if applicable, and or disease or survival status. Participants may be biopsied if abnormal results are found.

Other studies have demonstrated a benefit with PARP inhibitors in patients with some of these genetic abnormalities. At the 2019 ESMO Congress, findings from the phase III PROfound trial showed that the PARP inhibitor olaparib (Lynparza) doubled radiographic progression-free survival (rPFS) compared with physician's choice of abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in men with heavily pretreated metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations.²

In an interview with OncLive, Dahut, a senior investigator in the Genitourinary Malignancies Branch and head of the Prostate Cancer Clinical Research Section of the Center for Cancer Research at the NCI, discussed the natural history trial, the implications of the PROfound study, and the importance of screening for men at a high risk for developing prostate cancer.

OncLive: Could you discuss the rationale for the NCI-led study?

Dahut: We don't know how to best counsel men with known mutations, such as BRCA1/2 or ATM, that put them at a higher risk of developing prostate cancer.

In collaboration with the University of Washington, the University of Michigan, and Thomas Jefferson University, the NCI [is conducting] a natural history study of 500 men who have a known germline abnormality that [increases] their risk for prostate cancer, but do not currently have a prostate cancer diagnosis. These men will undergo MRI screening of the prostate every 2 years at NCI.

During the off year, PSA testing [will be conducted]. Interestingly, if we find an abnormality, we have the ability to integrate the tumor after biopsy for molecular characteristics, or other clues, which may indicate how the cancer will progress over time.

What did the preliminary findings from the prospective IMPACT study (Identification of Men with Genetic Predisposition to Prostate Cancer: Targeted screening in BRCA1/2 Mutation Carriers and Controls; NCT00261456) show?

Increasingly, data, such as from the IMPACT trial, have shown that men who have a BRCA2 mutation are a higher risk for prostate cancer without a doubt. In the IMPACT study, screening was conducted to determine whether men who had a PSA of ≥3.0 ng/mL had prostate cancer. Notably, nearly 50% of [the men screened] were found to have prostate cancer at the time of diagnosis.

We do not know what the correlation of PSA and a prostate cancer diagnosis is for men with BRCA2 or other mutations. We are using MRI to determine if that is a better tool to find cancer. [In turn], will that cancer be actionable earlier on?

How have the PROfound results impacted this space?

The data from the PROfound trial, which were presented at the 2019 ESMO Congress, clearly demonstrated that men who have a known germline or somatic mutation in the DNA damage response pathway and who progressed on a second-line androgen receptor inhibitor have longer rPFS and potentially longer overall survival with a PARP inhibitor [compared with men who were not treated with a PARP inhibitor].

This trial was immensely important to the medical community for 2 reasons. One, it showed that we can accrue to this type of a trial. Thousands of men were screened, and several hundred individuals were enrolled.

Secondly, it is going to have a cascade effect that will drive an increasing number of men with prostate cancer who had a germline abnormality identified by screening, [to relay the information] to their family members. Not only will it impact the men who have prostate cancer, but it has the potential to impact those who may develop cancer in the future.

What is the utility of MRI for screening prostate cancer?

MRI has been helpful in the diagnosis of prostate cancer. For years, the NCI has been doing multi-parametric MRI, which gives us the ability to look at an image of a prostate through MRI. Over time, a scoring system has been devised to look at each individual lesion and determine the likelihood of prostate cancer.

What is the role of MRI screening in the NCI-led trial?

We know we won't find all prostate cancers with MRI imaging. However, based on [previous] data, we know that MRI can find more cancer than PSA [testing]. Additionally, MRI is more likely to find lethal cancers. Data have also shown that MRI has the ability to find cancers for men with have high PSA but a negative biopsy. These cancers are not routinely biopsied by urologists.

In our study, we were particularly concerned that PSA may not be the best screening test for men with BRCA2 mutations who have a known increased mortality [rate]. By utilizing MRI, we anticipate we will identify more cancers earlier on.

Of course, we need [to be aware] that we are also going to detect cancers that are unlikely to progress. As such, we are spending a significant amount of time counseling patients prior to testing, and then going over the results in some detail.

Is the field working toward widespread awareness of genetic testing in prostate cancer?

As more men have learned that [the presence] of particular genetic mutations puts them at a risk for prostate cancer, more of them are approaching the primary care physicians or urologists about what next steps to take. Our clinical trial is attempting to get information that can be shared with the community. In turn, we hope to educate others about those next steps.

Published guidelines often recommend screening with a PSA at age 40 or 45. However, that is not based on data that will have long-term impact. Our hope is that by putting scientists together, [they will gather] the information [needed] to help educate patients going forward.

What is your hope for the future in terms of education and implementation of genetic screening?

My hope is that we will be able to personalize risk for all men, not just those with high genetic risk for prostate cancer. [I would like to be able] to inform men how and when they should be screened, and what to do with that information.

There is a justified fear in the United State about overscreening. If all men are screened in the same way and treated based on those findings, there is no question that overtreatment would occur.

If we can individualize screening and how [findings are interpreted], men may benefit. Subsequently, future clinical trials [exploring] chemotherapy prevention may delay or eliminate the need for more aggressive local therapies.

References

1. Hussain M, Mateo J, Fizazi K, et al. PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA12_PR.
2. Dahut WL, Couvillon A, Pinto PA, et al. Natural history and imaging in men with high genetic risk for developing prostate cancer. Can J Urol. 2019;26(suppl 2):7-8.