In this animated video from Dr Neal Shore, you'll follow a patient through their mCRPC journey and explore the clinical implementation of genetic testing and monotherapy treatment with a PARPi.

 

The GU CONNECT expert discusses:

  • Efficacy and safety profiles of PARP inhibitors for prostate cancer
  • The role of genetic testing and how to use it to assess HRRm status and influence treatment decision-making
  • Data from key PARPi mCRPC studies and the clinical implication of this data

 

Watch the video and download the accompanying slides below.

 

Clinical Takeaways

  • PARP inhibitors are effective drugs as monotherapy in mCRPC patients with HRR alterations
  • Genetic testing is important to inform on prognosis, help with treatment decision-making, and for understanding inherited risk
  • BRCA mutations are associated with poor outcomes in mCRPC patients
  • Patients with tumours harbouring BRCA1/BRCA2 alterations appear to derive the greatest clinical benefit from PARP inhibitor monotherapy, but patients with other HRR alterations might also derive benefit

PARP Inhibitor Monotherapy

Well, hi everybody. I'm Neal Shore. I'm the Medical Director of Carolina Urologic Research Center and Chief Medical Officer at GenesisCare in the U.S.

Today we're going to talk about the role of PARP inhibitors monotherapy for mCRPC, specifically for patients who have homologous recombination repair HRR mutations.

The patient we're talking about today had a first line treatment with the doublet of androgen deprivation therapy and abiraterone, of course, there are multiple doublet options and even in some places, we have triplet options.

This particular patient had a quite advanced disease, high volume mHSPC. No known family history of cancer. It's important to get a good family history these days because we know that a significant family history, breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, ovarian cancer, increases the risk of homologous repair alterations.

There are a lot of different potential options for patients who are mCRPC after they've gone undergone doublet therapy, this particular patient, ADT and abiraterone acetate and prednisone. A lot of different options.

It's very important to understand that we want to optimise the novel mechanisms of action and really not go forward with sequencing novel hormonal agents. We have data now that clearly demonstrates, whether it's the PROfound trial or CARD, that sequencing one NHA after another is nowhere near as effective as going to a novel MOA, such as a PARP inhibitor or a taxane, cabazitaxel in the CARD trial, PROfound demonstrating the value proposition for olaparib.

So if you have a patient who has an homologous recombinant repair or HRR mutation, they certainly could benefit from a PARP inhibitor. Testing is very important. Germline testing will pick up patients who have alterations early on. But if you have a negative germline, very important to move to somatic testing because otherwise, you'd miss 50% of your patients with metastatic disease. We can test with blood or with saliva for germline. Somatic - you can check with tissue-based testing, but if the tissue is not available, blood-based testing is very helpful.

We've recognised that genetic testing, particularly if you find a BRCA mutation, that these patients have clearly a worse prognosis. Patients who are BRCA positive, as this particular patient is, is now suitable for a PARP inhibitor monotherapy in first line or second line mCRPC.

We now have two PARP inhibitors that have been demonstrated level one evidence for their clinical utility for patients with castration-resistant disease, and this includes olaparib and rucaparib. And this has been demonstrated in the PROfound, TRITON2 and TRITON3 trials.

What we see is that with other trials as well, the use of sequencing is really not the best move.

PROfound demonstrated overall survival benefit, rPFS benefit, when we sequenced patients who had BRCA or ATM alterations as opposed to sequencing them with an androgen receptor targeted agent.

Similarly, a phase two study of TRITON2 and phase three trials of the TRITON3 demonstrated that offering a patient who had a BRCA alteration specifically as opposed to receiving, going against docetaxel but rather patients going on to receive a PARP inhibitor did markedly better.

There are unique adverse events of interest, inclusive of anaemia. CBCs need to be monitored. There are some mild to moderate GI side effects, but these are very manageable. So we have real clear indications now based upon EMA and FDA review. I think this is excellent.

And when we look at this particular case, this patient who was BRCA2, who then progressed after a doublet therapy of ADT and abiraterone, can now be an outstanding candidate for therapy in mCRPC with a PARP inhibitor.

So, I hope you found this particularly helpful. Thank you very much for your attention.

Neal D. Shore, MD, FACS is the Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina. Dr Shore has conducted more than 350 clinical trials, focusing mainly on GU Oncology, and serves on the Executive Boards of: Society of Urologic Oncology Board, Bladder Cancer Advocacy Network, and is Immediate Past President, Large Urology Group Practice Association. He is a founder for both: CUSP Clinical Trials Consortium, as well as for DASHKO, large urology practices data registries. He serves as the National Urology Research Director for 21st Century Oncology. He has served on the AUA Male Health Committee and the AUA Data Committee, the SITC Task Force for Prostate Cancer, the Bladder Cancer Advocacy Think Tank and the editorial boards of Reviews in Urology, Urology Times, Chemotherapy Advisor, OncLive, PLOS ONE(Academic Editor), Urology Practice, World Journal of Urology, and serves as Editor, Everyday Urology-Oncology. He has more than 200 peer reviewed publications and numerous book chapters; he performs peer review for Lancet Oncology, New England Journal of Medicine, European Urology, Journal Urology, Urology, BJUI, PCPD, and numerous other high impact scientific journals. A graduate of Duke University and Duke University Medical School, Dr Shore completed a 6-month clinical research fellowship in Pretoria, South Africa, and then completed his General Surgery/Urology training at New York Hospital Cornell Medical Center and at Memorial Sloan-Kettering Cancer Center in New York City. He is a Fellow of the American College of Surgeons.

Dr Neal Shore has received financial support/sponsorship for research support, consultation, or speaker fees from the following companies:

Abbvie, Astellas, Amgen, AstraZeneca, Bayer, BMS, Boston Scientific, Clarity, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care, Invitae, Janssen, Lantheus, Lilly, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Phosphorous, Photocure, Propella, PreView, Sanofi Genzyme, Sema4, Speciality Networks, Sesen Bio, Telix, Tempus, Tolmar and Urogen, Vaxiion.

Programme summary
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Other episodes in this series
Clinical implementation of testing and PARPi as monotherapy

Clinical implementation of testing and PARPi as monotherapy

Episode 1: Clinical implementation of testing and PARPi monotherapy

Current Episode
Clinical implementation of testing and PARPis in combination with NHAs

Clinical implementation of testing and PARPis in combination with NHAs

Episode 2: Clinical implementation of testing and PARP inhibitors in combination with NHAs

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