The Utility of Genetic Testing in Patients with Prostate Cancer

EP: 1.Case Presentation: A 64-Year-Old Man with Metastatic Prostate Cancer

EP: 2.Typical Presentations of Metastatic Prostate Cancer and Risk of Disease Progression

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EP: 3.The Utility of Genetic Testing in Patients with Prostate Cancer

EP: 4.Mutations in HRR-Related Genes in Prostate Cancer

EP: 5.Available Treatment Options for Chemotherapy-Naïve mCRPC

EP: 6.Olaparib Safety and Efficacy Data from the PROfound Trial

EP: 7.A Urologist’s Treatment Selection for Metastatic Prostate Cancer

EP: 8.Potential Use of PARP Inhibitors for First-Line Treatment of mCRPC

EP: 9.Current Challenges and Future Directions in Metastatic Prostate Cancer

Case Overview:

Initial Presentation (Jan 2017)

A 64-year-old man is found to have a firm bilateral prostate nodule of 1.8 mm on his routine physical exam

Clinical workup

PSA 109.1 ng/mL

Family history of prostate cancer (father, uncle)

Transrectal ultrasound (TRUS)-guided biopsy of the prostate confirms advanced adenocarcinoma of the prostate and Gleason score of 8 (4 + 4)/Grade Group 4

MRI is negative for pelvic LN involvement but positive for one 1.1-cm mediastinal supraclavicular LN (T2bN0M1a)

His ECOG PS is 1

Germline multigene testing of biopsy specimen revealed a BRCA2 mutation

Initial Treatment (starting Feb 2017)

Patient was started on leuprolide and abiraterone; scheduled for physical exam, PSA assessment, and imaging every 3 months.

By the second follow-up visit (6 months after initiating treatment; August 2017), PSA levels declined to 2.1 ng/mL and prostate nodule size was 1.4 mm.

Patient’s disease remained stable through August 2018 (18 months of treatment).

21- and 24-month Follow-up Notes (November 2018, February 2019)

Patient’s PSA levels increased to 46.9 ng/mL in 11/2018 and 73.7 ng/mL in 2/2019.

MRI revealed that the size of the existing positive LN increased to 1.3 cm, and revealed a new, faintly positive 0.9-cm para-aortic LN.

Given the recent findings and the patient’s known BRCA2 mutation status, the patient and clinician decide to initiate olaparib 300 mg BID.

Neal Shore, MD, FACS: Let’s review the utility of genetic testing in patients with prostate cancer. This is a really important topic. Let’s talk about the guidelines for testing. I think most would agree that the NCCN [National Comprehensive Cancer Network] has done a good job in evolving their recommendations for both germline and somatic testing. Right now, in 2022, it’s really not who do you test, who’s newly diagnosed, it’s who don’t you test for germline alterations. The answer is, if you’re in grade group 1 or grade group 2, so Gleason score 6, or 3 plus 4, and you have no significant family history of cancer, the NCCN says don’t get germline testing. Everyone else, grade group 1 and 2 with a significant family history of cancer—breast, ovarian, colorectal, prostate, male breast, upper tract, urothelial, melanoma, skin cancer, pancreatic cancer—you would get germline testing. Certainly, anybody who’s high-risk localized, you get germline testing. And anyone who has metastatic disease, de novo or recurrent, you get germline testing.

We presented some data, we had a podium presentation of 1000 patients studied prospectively. We presented it at ASCO [American Society of Clinical Oncology annual meeting] 2021 and at AUA [American Urological Association meeting] 2021. We basically came to the conclusion that we think all patients should be tested regardless of their grade group or their family history, because oftentimes family history is not reliable. It’s important to get when it is reliable, but it can be unreliable. And some patients and their caregivers and their partners just don’t know their family history. Some people are adopted. Then there’s always the chance that the histopathology report can have variable or different interpretations, so a 3 plus 4 might actually be a 4 plus 3. I even see second opinions where a 3 plus 3 has turned into a 4 plus 3. Or a 3 plus 4 can become a 4 plus 4. I’m a believer in democratizing germline testing to make it simpler. It’s gotten less expensive. That’s subjective, but it used to be in the thousands-of-dollars range. Now it’s only a few hundred dollars, so I think anyone diagnosed with localized prostate cancer, my personal opinion is they should get germline testing.

Now, somatic testing per the NCCN recommendation is to get it when you are resistant, so when you are castration resistant. It’s important because if you’re germline negative, you might pick up another 50% of patients with HRR [homologous recombination repair] mutations. We saw that about 28%, 30% in some centers have HRR mutations, and we saw that in the PROfound trial. Other trials and studies have corroborated that. For newly diagnosed, you’re probably going to see positive germline alterations in the HRR category of about 10% to 12%. So it’s important if you’re germline negative that you don’t stop there once the patient develops resistance, that you get either the archival tissue, prostate biopsy tissue, the prostatectomy specimen. Or you can get metastasis-directed biopsies. If you can’t get tissue or you can’t do a biopsy, then you can what we describe as a liquid biopsy, and you look for circulating DNA alterations.

This then opens up a field of opportunity of clinical utility because we now have level 1 evidence for the use of PARP inhibitors. We also have level 1 evidence for the use of a checkpoint inhibitor when there’s MSI [microsatellite instability]-high. We also have multiple trials ongoing with other alterations, such as ATM, PTEN loss, other alterations where we’re looking in a clinical trial landscape to come up with additional therapeutics. Then there’s the importance of cascade family testing. If there’s a germline alteration, you’d want to certainly know to inform the patient’s children, siblings, nieces and nephews. It would be great to be able to pick up a very early ovarian, breast or prostate cancer, pancreatic cancer, colorectal cancer, and cure that patient at its earliest stages.

How do the test results impact patient management? Well, exactly, if you have an alteration, it’s a pathogenic variant as opposed to a variant of uncertain significance. It can lead to approved therapies as I’ve described. It could lead to more vigilant surveillance or possibly an active intervention for localized disease. Or it certainly could lead to an approved indication of a therapy when the patient reaches that point in their journey.

Transcript edited for clarity.