Clinical Implementation of Testing and PARPi as Monotherapy or in Combination with NHAs
Clinical Implementation of Testing and PARPi as Monotherapy or in Combination with NHAs
The prostate cancer patient journey
The prostate cancer patient journey
Dr Neal Shore, Dr Andrew J. Armstrong
In these animated videos from Dr Neal Shore and Dr Andrew Armstrong, you'll follow a patient through their mCRPC journey and explore the clinical implementation of genetic testing and PARPi as monotherapy and in combination with novel hormonal agents (NHAs).
The GU CONNECT experts discuss:
- 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 decision-making
- Data from combination studies with PARPis and NHAs in metastatic mCRPC
- The rationale, mechanism of action and implementation of therapy combinations
- How combination therapy impacts clinical practice
Watch the videos and download the accompanying slides below.
Dr Neal Shore
Urologist
Carolina Urologic Research Center and GenesisCare
United States (US)
Dr Andrew J. Armstrong
Medical Oncologist
Duke University School of Medicine
United States (US)
Clinical implementation of testing and PARPi monotherapy
Video | 
5 min
|
Aug 2023
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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.
Clinical implementation of testing and PARP inhibitors in combination with NHAs
Video | 5 min
|
Aug 2023
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PARP inhibitors in Combination with NHAs
Hello, I’m Andrew Armstrong, a medical oncologist at Duke University in the United States.
I’d like to take you on a patient journey, looking at combination novel hormonal agent use with PARP inhibition starting with a case. We have a 66-year-old gentleman who presents with de novo metastatic hormone sensitive prostate cancer. He’s got a strong family history of breast cancer, PSA of 110, and you treat him for his metastatic disease with chemo hormonal therapy.
However, he starts to progress within a year with a PSA that rises from 0.2 to 14, and now you’re faced with metastatic castrate resistant prostate cancer in this patient. You’re now going to consider a potent AR inhibitor such as abiraterone or enzalutamide. As I choose between abi and enza, I recognise that the efficacy data for these choices in men with the mCRPC is very similar.
The risks and benefits of choosing between abiraterone and enzalutamide have been clear for many years, where the risks are largely known and associated with the use of prednisone for abiraterone, mineralocorticoid excess, metabolic side effects and immune suppression. While enzalutamide can result in increased fatigue, falls, hypertension and some cognitive effects. And therefore, the choice may depend on drug-drug interactions, co-morbidities, costs and patient preference.
It's important to realise that, as we treat men with advanced prostate cancer, genetic testing is now standard of care and recommended by all international guidelines. This typically is germline testing in all men, either saliva or blood testing, or tumour or liquid biopsy testing that can identify somatic only alterations that may be actionable and guide the use of PARP inhibitors or PD-1 inhibitors. We recommend germline testing in all men with metastatic prostate cancer, and our case underwent germline testing and identified a pathogenic BRCA2 mutation. This explains his family history and his presentation with more aggressive prostate cancer. We know that men with mCRPC and a BRCA2 mutation tend to have worse outcomes with monotherapy with an NHA.
The current data support the use of NHA PARP combinations in the first line setting for mCRPC patients like our case, who have a pathogenic BRCA mutation. There are a number of trials that have now been completed and either published or presented that have demonstrated significant benefits to our patients in this setting from the combinations.
We have TALAPRO-2, PROpel and the MAGNITUDE study, each of which has shown benefits, particularly in BRCA2 patients, but also in patients with homologous repair deficiencies and even in an unselected patient population in the TALAPRO-2 and PROpel studies. We have combination therapies with either abi plus olaparib or talazoparib plus enzalutamide in all-comers, and we have particular benefits as seen in delays in rPFS and improved overall survival in patients in the TALAPRO-2 and in the PROpel studies.
This table describes the different hazard ratios and improved outcomes for all-comer patient populations, as well as subgroups defined by homologous repair and BRCA alterations, where you can clearly see greater magnitudes of benefit in those patients that have BRCA mutations. Now these are cross-trial comparisons. They are not meant to be comparable, but you can see differences in efficacy across these studies in relatively similar patient populations.
When we look at the TALAPRO-2 and PROpel studies that were positive for their primary endpoint of delaying rPFS in a biomarker unselected population, we see very similar hazard ratios, whether we look at independent blinded review or using investigator assessments. The hazard ratios are very similar, suggesting greater benefits in delaying radiographic progression or death with the combination as compared to an ARSI monotherapy.
However, for MAGNITUDE, which uses niraparib, we saw no clear benefits of the combination, suggesting that for that PARP inhibitor, the benefits were isolated to the BRCA population.
When assessing the benefits of delaying progression, it's also important to look at, is there a benefit on survival and is there greater benefits to the patient over risks? In PROpel the most mature of the data sets, we saw a 7.4 month survival advantage. The overall survival data is not mature yet in TALAPRO-2 and MAGNITUDE and the greatest survival advantage, again, was seen in the BRCA mutated patients with a hazard ratio of 0.29, a substantial delay in the risk of dying of prostate cancer with those men with BRCA2 mutations who were treated with the combination of abiraterone and olaparib.
When trying to decide between the PARP and AR combinations, largely we're going to be making decisions based on efficacy, but also based on safety. We know that PARP inhibitors can cause cytopenias, particularly anaemia, which we see greater proportions of patients experiencing with talazoparib followed by niraparib, followed by olaparib. And again, cross-trial comparisons can be different, but at least for safety, the adverse event reporting system is very similar. We can also see nausea, vomiting and fatigue among the more severe adverse events that are a class effect of these combinations.
In the end, our patient will be faced with that choice of a potent AR inhibitor, plus a PARP inhibitor based on his own preferences, the availabilities and the co-morbidities of that patient. There is no right or wrong answer here. This patient should be offered combination, more intensive therapy with the PARP inhibitor because of his BRCA mutation. I'd like to refer you to our slide deck for great details about the efficacy and safety of these combinations.
Thank you.
Clinical Takeaways
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PARP inhibitors are effective drugs as monotherapy in mCRPC patients with HRR alterations
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Genetic testing is important to inform on prognosis, help with treatment decision-making, and for understanding inherited risk
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BRCA mutations are associated with poor outcomes in mCRPC patients
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Patients with tumours harbouring BRCA1/BRCA2 alteration appear to derive the greatest clinical benefit from PARP inhibitor monotherapy, but patients with other HRR alterations might also derive benefit
- PARP inhibitors combined with novel hormonal agents are also effective as a 1st line treatment option for mCRPC patients with an HRR mutation. Certain combinations, such as olaparib plus abiraterone, have also shown benefit in patients regardless of their HRR status
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This educational programme is supported by an Independent Medical Education Grant from AstraZeneca
GU CONNECT is an initiative of COR2ED, supported by an Independent Educational Grant from AstraZeneca, Bayer and Eisai Europe Limited.
Other programmes of interest
2 min
Other programmes developed by Dr Neal Shore
Dr Neal Shore
Urologist
Carolina Urologic Research Center and GenesisCare
United States (US)
Other programmes developed by Dr Andrew J. Armstrong
Dr Andrew J. Armstrong
Medical Oncologist
Duke University School of Medicine
United States (US)
