Role of Molecular Testing in mCRPC

EP: 1.Case Overview: 62-Year-Old Man With Metastatic CRPC

EP: 2.Monitoring Patients With mCRPC

EP: 3.Frontline Treatment Options for mCRPC

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EP: 4.Role of Molecular Testing in mCRPC

EP: 5.ARAMIS and ODENZA Trials in CRPC

EP: 6.Using Darolutamide in Clinical Practice for mCRPC

EP: 7.Approaching Systemic Therapy for mCRPC

EP: 8.Future Directions for the Treatment of mCRPC

Tomasz M. Beer, MD, FACP: The question about molecular or biomarker testing is a wonderful question. NCCN [National Comprehensive Cancer Network] Guidelines nowadays endorse recommending germline genomic testing for patients with metastatic prostate cancer and with high-risk locoregional disease as well. We would expect to find a mutational genetic predisposition to cancer in 10% to 12% of patients in that situation. Certainly germline testing would have been appropriate.

The other type of testing is somatic testing, looking for mutations that are not just inherited but also potentially acquired in the tumor. That can be done through an analysis of tumor tissue, or it can be done through a so-called liquid biopsy or blood-based analysis of circulating tumor DNA. That’s typically done with the goal of treatment selection, and there are a couple of treatments that are molecularly selected. One is PARP inhibitors. There are 2 that are approved, olaparib and rucaparib. Another is pembrolizumab, an immune checkpoint inhibitor.

PARP inhibitors can be helpful for patients with mutations in some of the key genes for DNA repair, and the evidence is most clear for BRCA2 and BRCA1 mutations. Immune checkpoint inhibitor therapy would be appropriate to consider in patients who have a hypermutated phenotype. Microsatellite instability is another term that’s often used to identify patients who have a very high mutational burden, and presumably a larger number of abnormal antigens formed through mutations and the making of abnormal proteins, making it more responsive to immunotherapy. That’s the indication for somatic analysis.

These kinds of therapies are typically done at the earliest after progression on a next-generation androgen signaling inhibitor—so not yet in our patient—and in many cases after a round of chemotherapy as well. I’m not sure if there’s an immediate imperative to do somatic mutational testing at this point in the course of his treatment. One could certainly contemplate that to gather that information for the future, but 1 could also do that later. Germline testing for inherited mutations would certainly be recommended. It would be potentially helpful for this patient’s treatment but also to family members.

The question is about a patient like this who is older and has additional comorbidities. This is a common scenario. Many patients with prostate cancer are older than age 62, especially patients with recurrent metastatic disease. These are often folks who had a prostatectomy maybe a decade ago and have had a PSA [prostate-specific antigen] or so-called biochemical relapse and eventually develop metastatic disease. By then they’re often in their mid 70s and beyond. One of the principals of geriatric oncology is to think about biologic age rather than chronologic age. We don’t just treat older folks differently because the number is higher. We look at their health and comorbidities. Of course, comorbidities are more common as people get older, but we do need to consider the healthy, robust 80-year-old as someone who is capable of withstanding all the usual therapies and deserving of that.

In people with compromised organ function or significant comorbidities, we can think about selection of agents. We’ll be a bit less likely to recommend docetaxel chemotherapy. We may think about carefully between abiraterone and apalutamide or enzalutamide in this setting, and the choice there might depend on the types of comorbidities. An example would be folks with diabetes may have a bit of a tougher time with abiraterone because of the prednisone and the blood sugar control issues that develop. Folks with preexisting cardiovascular conditions are at elevated risk on either agent, but the risk is greater with abiraterone, so we may lean toward apalutamide or enzalutamide there. On the other hand, enzalutamide and apalutamide have been associated with an increased risk of falls, so people who are frail and have had a history of falls might be better candidates for abiraterone. That’s a complex discussion, but it would definitely require us to think carefully about which drugs to choose.

I’d be reluctant to omit the doublet therapy unless truly forced to do so. There’s a clear benefit in terms of progression-free survival and overall survival, and metastatic prostate cancer is an aggressive, lethal disease. In an uncommon scenario, even in an 80-year-old with comorbidities, I would recommend leuprolide alone. It certainly has happened, but usually we would work hard to find a way to safely deliver the most effective anticancer therapy.

Transcript Edited for Clarity

A 62-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

Jan. 2017

Initial presentation

• A 62-year-old man is found to have a firm prostate nodule of 1.5 mm on his routine physical exam

Clinical workup

• PSA 15.5 ng/mL
• Family history of prostate cancer
• Hypertension
• Digital rectal exam and transrectal ultrasound (TRUS) of the prostate confirm advanced adenocarcinoma of the prostate and Gleason score of 7 (3 + 4)
• MRI shows lack of metastasis and node involvement (cT2bN0M0)
• His ECOG PS is 1

Treatment

• In Feb. 2017, patient was treated with radical prostatectomy (RP) with nerve sparing surgery and there were no complications.
• PSA levels go down to 0.3 ng/ml post-operatively but rise to 1.5 ng/ml within 3 months.
• Patient receives local salvage radiation therapy and PSA goes down to 0.1 ng/ml.
• PSA levels are checked every 3 months.

Nov. 2017

• PSA doubling time increased between 2 last check-ups and now PSA is 3.5 ng/ml.
• Patient undergoes CT and bone scans and is found to 1 metastatic bone lesion.
• Patient is treated with androgen deprivation therapy (ADT), leuprolide, as continuous treatment and PSA levels go down to 0.2 ng/ml.

May 2018

• PSA levels rise to 5 ng/ml, but patient is asymptomatic and has adequate organ and bone marrow function.
• Patient meets the inclusion criteria for the ODENZA trial and is enrolled in it.
• Patient is treated with darolutamide(1200 mg/day) for 12 weeks, followed by enzalutamide (160 mg/day) for 12 weeks, in addition to continuing on ADT
• Patient is currently in the extension phase of the study and is being treated with darolutamide.