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Current Challenges and Future Directions in Metastatic Prostate Cancer


Neal Shore, MD, FACS, muses about the unmet needs in metastatic prostate cancer treatment and shares clinical pearls for community oncologists.

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: The biggest challenge is that patients will die. And unfortunately, even if they get exposed to now all of the novel mechanisms of action, and we are challenged to still understand how to best combine some of these, how to sequence. Ultimately, if the patient has good cardiovascular health and an intact bone compartment so they’re not becoming overly myelosuppressed, they ultimately will succumb to the disease. But we’ve made great progress. The median overall survival for an asymptomatic patient with mCRPC [metastatic castration-resistant prostate cancer], which was 19 months in 2010, is now closer to 3-and-a-half years in 2022. It’s a virtual doubling. We have many patients now who are living 5, 6, 7 years with advanced prostate cancer, especially those even with CRPC. So we’re making great strides, but ultimately, we’re not curing the disease. That’s why clinical trials are a standard of care. I certainly implore all of my colleagues to think about clinical trials whenever possible.

In terms of future directions, besides earlier use of PARP inhibitors, are there any other interesting drugs or combinations in the pipeline addressing the unmet needs? Gosh, there are so many. There’s some great work going on with CDK4/6 inhibition. There’s work going on with ATM, ATR pathways, PTEN loss, PI3K, AKT pathways, and a lot of really good work looking at combining other therapies to lessen resistance. That I think is one of the interesting aspects of taking a PARP inhibitor in combination with an AR [androgen receptor] pathway inhibitor, increasing the responsiveness of a PARP inhibitor to a patient who’s HRR [homologous recombination repair] negative, while at the same time adding a PARP inhibitor and decreasing the likelihood of developing AR resistance. Is there a difference among the PARP inhibitors? A lot of this work remains to be investigated, discussed, and described.

Finally, what clinical pearls do I have for community oncologists treating patients with metastatic CRPC? I would say it’s an incredible time to be importantly current with the literature. At ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], we saw 3 incredibly important studies, PROpel, MAGNITUDE, ARASENS. There are additional studies that’ll be forthcoming in virtually every one of our major congresses, which will allow us to have an even more full-throated conversation with patients regarding their options. We recently had the approval of lutetium-617, the first phase 3 trial demonstrating survival benefit utilizing the novel mechanism of action of a PSMA ]prostate-specific membrane antigen] radioligand therapy. That adds yet another, or what I would describe as the seventh, novel mechanism of action for patients with advanced prostate cancer. We now have 12 life-prolonging agents to pick from within the 7 novel mechanisms of action.

The challenge to our community oncologists, whether they’re radiation oncologists, urological oncologists or medical oncologists, is to make sure that if your patient succumbs to advanced prostate cancer, that he doesn’t just have 1 to 2 level 1 evidence-approved therapies, but that indeed he got as many of the 7 novel mechanisms of action as possible. It’s also important that we are able to be really good stewards of the adverse effect, safety profiles that are unique to each of them, and to offer them in a way that’s propitious. Then of course globally, we’re all challenged with trying to get access to these new drugs, which is oftentimes challenging because of accessibility, either physically or economically. As physician-scientists, that’s a high priority for all of us.

Thank you very much. I appreciate your attention.

Transcript edited for clarity.

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