A urologist’s treatment selection for metastatic prostate cancer
Initial presentation (January 2017)
A 64-year-old man presents with a 1.8 mm firm bilateral prostatic nodule during his routine physical examination.
PSA 109.1 ng/mL
Family history of prostate cancer (father, uncle)
Transrectal ultrasound-guided prostate biopsy (TRUS) confirms advanced prostate adenocarcinoma and a Gleason score of 8 (4+4)/Grade Group 4
MRI is negative for pelvic LN involvement but positive for a 1.1 cm mediastinal supraclavicular LN (T2bN0M1a)
Its PS ECOG is 1
Germline multigene testing of a biopsy specimen revealed a BRCA2 mutation
Initial treatment (from February 2017)
The patient was put on leuprolide and abiraterone; scheduled for physical examination, PSA evaluation and imaging every 3 months.
At the second follow-up visit (6 months after treatment initiation; August 2017), PSA levels decreased to 2.1 ng/mL and prostate nodule size was 1.4 mm.
The patient’s disease remained stable until August 2018 (18 months of treatment).
Follow-up notes at 21 and 24 months (November 2018, February 2019)
The 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 existing positive LN increased in size to 1.3 cm and revealed a new slightly positive para-aortic LN of 0.9 cm.
Given recent findings and the known condition of the patient BRCA2 mutation status, patient and clinician decide to initiate olaparib 300 mg twice daily.
Neal Shore, MD, FACS: Given the treatment options available, what treatments would I have chosen for this patient? I think this is a patient for whom it makes perfect sense to start with ADT. [androgen deprivation therapy] and abiraterone. He reacted well for about a year and a half, then he clearly shows progress. New lymph node involvement, PSA [prostate-specific antigen] getting up and being BRCA2 [mutation positive], I think he is an ideal candidate to start treatment with olaparib. In my experience, most patients still prefer oral medication over intravenous medication, a particularly compelling argument during a pandemic. I am a big proponent of taxane therapies and explain to patients that they will be part of their regimen. But I think when you have the ability to have personalized medicine, a bespoke therapy based on precision, where there’s a genetic alteration that allows you to specifically benefit from it, 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 he’s a patient with lymph node metastases.
An interesting question that arises is: if you selected olaparib for this patient, who is now the first-line mCRPC [metastatic castration-resistant prostate cancer] because he received his mCSPC [metastatic castration-sensitive prostate cancer] ADT/abiraterone combination, would you stop abiraterone and leuprolide? All of our trial literature, prostate cancer working group definitions, would say absolutely don’t discontinue ADT. But we don’t have enough level 1 evidence to say whether we continue abiraterone. We don’t know if that’s right or wrong, quite frankly. There was recently some 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, considering combining in first-line mCRPC 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 what treatment you chose if you did not know BRCA2 state of mutation? Would you like to perform biomarker tests before starting treatment? Absolutely, this is the perfect time if I hadn’t had a germline test, to frankly do the somatic test. Get the fabric. If you didn’t have the handkerchief, make the cash. So if I found BRCAabove all BRCA2absolutely offer the patient a treatment based on olaparib, also known commercially as Lynparza.
What other treatments would I have considered with a mutation of another HRR [homologous recombination repair]-related genes, such as ATM, CHEK1, CHEK2, CDK? That’s an excellent question. I would say we see patients who respond with ATM, CHEK1, CHEK2, CDKperhaps nowhere near as robust as we see it with BRCA2. But it is an option to consider. It is now a labeled indication. There are about ten other genetic alterations. I said to the patient, “Listen, let’s see if it works for you. It won’t work for everyone. It’s not 100%. But why not try? We know the safety and adverse event profile. We’ll see if it works. We will monitor PSA. We see PSA around 50 [ng/mL] in about 50% of patients. We are also looking for the stability of the PSA. We are looking for imaging stability in subsequent radiographic testing, and we certainly want to see a clinical benefit, that the patient is not clinically deteriorating.
I am prescribing olaparib now, after approval, over 2 years. I really like that. It’s another tool in the toolbox. I tell patients look, we have a lot of tools now. I want to make sure to optimize all the new mechanisms of action. I think that’s where the data indicates that if you succumb to the disease, you’ll be much better off if you’re exposed to as many new mechanisms of action as possible. And clearly, PARP inhibition is distinctly different from AR [androgen receptor] pathway drugs, distinctly different from taxanes, radiopharmaceuticals, and immunotherapies, whether sipuleucel-T or a checkpoint inhibitor.
Transcript edited for clarity.