A focused discussion on the significance of mutations in homologous recombination repair (HRR)-related genes in prostate cancer.
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
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 discuss the importance of the homologous recombinant repair [HRR] pathway in healthy cells. How do the alterations in this pathway relate to cancer? Very interestingly, when there’s an alteration in the HRR pathway, or what we call oftentimes the PARP pathway, defective cells are allowed to replicate. And the defective cells that replicate when there’s a PARP alteration as part of the HRR pathway can be stopped, can result in abrogation of that faulty replication. We sometimes use this expression of synthetic lethality. When you have faulty replication because of a defect in the HRR pathway, which is also affecting the PARP enzymes, and you add a PARP inhibitor, that doesn’t allow the pathway to continue in its faulty replication of defective cancerous cells. That ultimately leads to the synthetic lethality.
What are some of the most common HRR-related genes included in the biomarker testing? It’s BRCA2, BRCA1, ATM, PALB2, CDK12, CHEK1, CHEK2. There are several of them, the RAD50. And we continue to learn. A lot of the less-common gene alterations, we still need to aggregate these findings to ultimately see the actual benefit of using either a PARP inhibitor or some targeted therapies that are under investigation, such as the ATR pathway. Additionally, checkpoint inhibition, some of the PD blockers as well. We’ve seen some interesting results, for example with CDK12. We do need to continue to aggregate that data.
Are there any genetic mutations that are particularly informative or impactful for prognosis or risk stratification and treatment selection? Yes, I think that based upon the PROfound trial and based upon the TRITON2 trial, a very well-done open-label phase 2 study looking at another PARP inhibitor. Olaparib was the PARP inhibitor in PROfound; rucaparib is the PARP inhibitor in TRITON. One saw, again, very significant PSA [prostate-specific antigen] responses in the TRITON2 for the BRCA2, BRCA1 population, as well as objective responses and delays in radiographic progression. There’s a confirmatory trial known as the TRITON3, which is ongoing. But because of the TRITON2 and the PROfound trials, the FDA gave approval in May of 2020 for both of these drugs in the mCRPC [metastatic castration-resistant prostate cancer] population. Olaparib was approved for patients with mCRPC who progressed after a novel hormonal agent, and rucaparib for patients who progressed after a novel hormonal agent who have mCRPC and also who have progressed after receiving a taxane, typically docetaxel.
Transcript edited for clarity.