A 64-Year-Old-Man with Metastatic Prostate Cancer - Episode 7

A Urologist’s Treatment Selection for Metastatic Prostate Cancer

Dr Neal Shore shares how he would have treated the patient with metastatic prostate cancer from the presented case.

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: Given the available treatment options, which treatments would I have selected for this patient? I think this is a patient for whom it’s perfectly reasonable to begin with ADT [androgen deprivation therapy] and abiraterone. He responded well for about a year-and-a-half, and then clearly is demonstrating progression. New nodal involvement, PSA [prostate-specific antigen] rising, and being BRCA2 [mutation positive], I think he’s a perfect candidate to begin treatment with olaparib. Most patients still, in my experience, prefer an oral medication to an intravenous medication, particularly a compelling argument during the time of the pandemic. I am a big believer in taxane therapies, and I explain to patients that they will be part of their regimen. But I think when you have the ability to have personalized medicine, precision-based, tailored therapy, where there is a gene alteration that allows you to specifically benefit, why not invoke that? One can still invoke a short course of Provenge at some point; if the patient had bone metastases, radium-223, but this is a patient with nodal metastases.

An interesting question coming up is, if you selected olaparib for this patient, who’s now first-line mCRPC [metastatic castration-resistant prostate cancer] because he received his mCSPC [metastatic castration-sensitive prostate cancer] combination ADT/abiraterone, would you discontinue the abiraterone and leuprolide? All of our trial literature, prostate cancer working group definitions, would absolutely say do not discontinue the ADT. But we don’t have enough level 1 evidence to say do we continue the abiraterone. We don’t know that it’s wrong or right, quite frankly. There was recently data presented that I’m going to get to called the PROpel trial. We’ll talk more about that. Very fascinating data came out of ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] 2022, looking at combining in the mCRPC first line a PARP inhibitor with abiraterone. One was the PROpel trial with olaparib and abiraterone, and the other was the MAGNITUDE trial with niraparib and abiraterone.

Another question for this patient would be, which treatment you have chosen if you did not know the patient’s BRCA2 mutation status? Would you perform biomarker testing before initiating treatment? Absolutely, this is a perfect time if I hadn’t had any germline testing, to quite frankly do the somatic testing. Get the tissue. If you didn’t have the tissue, then do the liquid based. Then if I found BRCA, especially BRCA2, absolutely offer the patient a treatment with olaparib, also known commercially as Lynparza.

What other treatments would I have considered with a mutation of other HRR [homologous recombination repair]-related genes, such as ATM, CHEK1, CHEK2, CDK? That’s a great question. I would say we see some patients who respond with ATM, CHEK1, CHEK2, CDK, maybe nowhere near as robustly as we see with BRCA2. But it is an option to consider. It is now a labeled indication. There are about another 10 or so other gene alterations. I would say to the patient, “Look, we’re going to see if this works for you. It’s not going to work in everybody. It’s not 100%. But why not give it a try? We know what the safety, adverse event profile is. We’ll see if it’s working. We’ll monitor PSA.” We see PSA around 50 [ng/mL] in about 50% of the patients. We look for stability of the PSA as well. We look for stability of imaging on subsequent radiographic testing, and we certainly want to see clinical benefit, that the patient’s not clinically deteriorating.

I’ve been prescribing olaparib now, post-approval, closing in on 2 years. I really like it. It’s another tool in the toolbox. I tell patients that look, we’ve got many tools now. I want to make sure that I optimize all the different novel mechanisms of action. I think that’s where the data say that if you’re going to succumb to the disease, you’ll do a lot better if you’re exposed to as many novel mechanisms of action as possible. And clearly, PARP inhibition is distinctly different from the AR [androgen receptor] pathway drugs, distinctly different from the taxanes, from radiopharmaceuticals, and from immunotherapies, whether it’s sipuleucel-T or a checkpoint inhibitor.

Transcript edited for clarity.