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Available Treatment Options for Chemotherapy-Naïve mCRPC


Neal Shore, MD, explains the available first-line treatment options for chemotherapy-naive, metastatic castration-resistant prostate cancer (mCRPC).

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 briefly review the available treatment options for chemotherapy-naive mCRPC [metastatic castration-resistant prostate cancer]. Let’s take a high-level view of those options. If you’re chemotherapy naive and you have mCRPC in the United States, you have now what many would call an embarrassment of riches. We try to taper and pick the therapy based upon, importantly, tumor burden, location of the disease, the patient’s comorbidities, patient preference. Are they suffering from heart failure and fluid retention? Do they have diabetes? Do they have symptomatic bone disease? Do they have visceral metastases? And so, we have this embarrassment of riches, and it can include, in the United States alone, there’s sipuleucel-T. We also have for patients who have bone-predominant disease, radium-223. Of course, we have the novel hormonal agents inclusive of enzalutamide and abiraterone acetate.

Then you have the PARP inhibitors. As we demonstrated in the PROfound trial, PARP inhibitors are extremely effective in the BRCA2, BRCA1 [gene mutations]. There was benefit seen in the other gene alterations, enough such that the FDA allowed for 14 gene alterations to meet the panel for PARP inhibition. Now interestingly in PROfound, the overwhelming majority of patients received their novel hormonal agent, abiraterone or enzalutamide, in first-line mCRPC. But you can receive abiraterone or enzalutamide, or frankly even apalutamide, in the mCSPC [metastatic castration-sensitive prostate cancer] space and progress from castration sensitive to resistant. And if you have an HRR [homologous recombination repair] alteration, you can receive olaparib. So, you don’t have to have only received it in the castration-resistant state.

What’s the rationale for the use of PARP inhibitors in prostate cancer? I think we’re always trying to be as precise or personalized or tailored to our treatment. So, if we know that someone’s sensitive to a specific targeted pathway, why not use it? If we know that they’re not sensitive to a specific targeted pathway, then why use it? Ninety-nine percent of patients respond to T-cell suppression, but then they develop resistance. Not everyone responds to an AR [androgen receptor] pathway drug. We’ve seen some splice variants, for example AR-V7, which may confound or diminish the benefit of an AR pathway drug. There are types of gene alterations that are particularly sensitive only to a certain therapy, and that would be a PARP inhibitor. The bottom line there is if you don’t test, you’ll never know. So, it’s extremely important to do the testing. You do the germline testing because of the importance of finding clinical utility. Now that we have level 1 evidence for patients who progress to resistance, they can benefit from a PARP inhibitor. But if you’ve never tested germline and then germline was tested but negative, you still need to test for somatic. Then there’s the importance of notifying family members to test and maybe picking up an early localized cancer in prostate, but other organ systems too, and help that person cure their disease early.

Transcript edited for clarity.

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