mCRPC in focus
Transcript: Is precision oncology benefiting the mCRPC treatment landscape?
Professor Neeraj Agarwal
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
Precision oncology has come to the forefront of prostate cancer medicine fortunately. For a long time we were lagging behind many other cancer types, including haematologic cancers, or thoracic oncology, or even GI oncology, breast oncology, where precision medicine has been used for almost a decade.
So in prostate cancer, the precision oncology started with obviously approval of olaparib and rucaparib; both PARP inhibitors which were approved for patients with homologous recombination repair gene mutations of multiple types, in the case of olaparib, and for rucaparib they were approved for patients who had BRCA1 and BRCA2 mutations, and after they had disease progression on chemotherapy. Although we have only have two approvals from precision oncology perspective, as far as genomic mutations are concerned, we should not forget about the Lutetium-177 therapy.
The radiopharmaceutical therapy, which is also precision oncology. It's not precision oncology based on genomic mutations, but it is precision oncology based on functional imaging. So patients who have high SUV or high PSMA expression as assessed by the PSMA PET scan imaging of the metastatic prostate cancer, are now eligible for treatment with Lutetium-177, after their disease has progressed on novel hormonal therapy, and chemotherapy with taxanes. But beyond that, there are multiple other clinical trials going on, and one of them, which is the PROpel trial, has recently led to approval of olaparib plus abiraterone combination for patients who harbour BRCA1 and BRCA2 mutations in their tumours. And this was based on, as I said, phase 3 PROpel trial, which included patients who were in in first line mCRPC setting. So they had a newly diagnosed metastatic castrate-resistant prostate cancer, and they were randomised to abiraterone plus placebo, versus abiraterone plus olaparib.
And they did genomic testing of the tumour in a retrospective fashion. And although PROpels showed benefit regardless of tumour mutations, or HRR mutations in the tumour, the approval label only include patients who have BRCA1 and BRCA2 mutations. Regardless, with the approval of abiraterone plus olaparib combination, the PARP inhibitors have now moved from before, from after novel hormonal therapy to a newly diagnosed mCRPC setting. But stories don't wanna stop here. We just saw MAGNITUDE trial showing benefit of abiraterone plus niraparib combination for patients with BRCA1, BRCA2 mutation, and other HRR mutations. We saw TALAPRO-2 study, another phase 3 trial, which led to enzalutamide plus talazoparib combination showing benefit over enzalutamide plus placebo in patients regardless of homologous recombination repair mutations, and in patients who were homologous recombination repair or DNA repair mutations.
The benefit was present in different type of HRR mutations. So beyond BRCA1 and BRCA2, we saw benefit in CDK12 mutation, patients who had CDK12 mutations, patients who had PALB2 mutations, and quite striking benefit. For example, there was a 50% reduction in risk of progression or death with enzalutamide plus talazoparib in patients in first time mCRPC with CDK12 mutation. I don't think this degree of benefit has ever been shown by any other combination or any other PARP inhibitors. But then we are also seeing other targeted therapies, or molecularly targeted therapies which are being tested in large phase 3 trials in prostate cancer.
So for example, CAPItello-281 trial is testing the combination of abiraterone plus minus capivasertib, an AKT inhibitor, in patients with mCSPC, with or without PTEN deficient in patients with mCSPC, with PTEN deficient tumours. And then there are other PARP inhibitor trials which are going on in the hormone sensitive setting in patients who are harbouring these DNA repair or homologous recombination repair mutations. And also patients who have high SUV uptake on the PSMA PET scan. And those patients are being randomised to standard of care, plus minus Lutetium-177 in the metastatic CSPC setting. So I think precision oncology has really started with full force for our patients with metastatic prostate cancer, and we expect these studies leading to approval of many of these precision medicine-based targeted therapy for our patients with prostate cancer in the very near future.
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