Over the last few years several studies have identified and confirmed that a proportion of patients with advanced prostate cancer harbour genetic alterations in key genes for the DNA repair pathway, particularly in those genes involved in homologous recombination repair. We know that tumours that have impaired homologous recombination repair are a good target for treatment with PARP inhibitors and that was the trigger for the clinical development of these compounds in prostate cancer.
How did the PROfound trial screen patients suitable for treatment with olaparib?
In the PROfound trial, which is the randomised phase III trial of olaparib in advanced prostate cancer, we screened patients from all over the world based on a targeted next generation sequencing panel using tumour tissue samples from patients either from their original diagnostic biopsies or, in a small number of patients, metastatic biopsies that were conducted for the trial.
What were the key outcomes in terms of survival between the groups treated with standard hormone therapy versus olaparib?
In the PROfound study we observed that those patients receiving olaparib had a prolonged time to radiographic progression and also a prolonged overall survival time compared to those who received a second hormonal agent that was the control arm. That was true primarily for patients in cohort A of the trial that was the key cohort and that included patients with mutations either in BRCA1, BRCA2 or ATM. However, subgroup analysis has shown later that patients with BRCA1 and BRCA2 mutations are the ones deriving the most benefit.
Apart from BRCA and ATM mutated prostate cancer is there any evidence that olaparib can be effective in causing synthetic lethality in other types of prostate cancer?
In the PROfound trial as well as in other phase II trials of olaparib and other PARP inhibitors we have seen consistently responses among patients who have mutations beyond BRCA1 and BRCA2. However, when you analyse those as a group, clearly BRCA1 and BRCA2 mutated tumours are the ones where we see the biggest benefit. In patients with ATM or CDK12 mutations that are very common in prostate cancer we have seen some patients responding really well and some of them are achieving good benefit. But actually when you put them together as a group there seems that the benefit is relatively short and not a significant difference in the overall study.
On the other hand we also have an issue with patients that have mutations in very uncommon genes or genes that are very uncommonly altered such as PALB2, RAD51, RAD54 that we know from preclinical studies and also from clinical studies that respond very well to PARP inhibitors but because these mutations are so uncommon the number of patients in the study are very, very small and it’s very difficult to do a gene per gene analysis for these subsets.
How would the clinical treatment of prostate cancer change after seeing the outcome of the PROfound trial?
The biggest change in clinical practice we’re going to be seeing as a consequence of the PROfound trial is the implementation of genomic testing based on tumour samples or liquid biopsies, but the genomic stratification of prostate cancer patients to identify those patients who could be good candidates to receive this therapy. It is not going to replace the standard of care but it will actually be an additional option of therapy for some of these patients with lethal prostate cancer.
What’s new since ASCO in the treatment of prostate cancer?
Over the last few months at several congresses very exciting data has been presented. At ESMO we have seen, on the one side, the confirmation of the PROfound results in terms of overall survival, brief updates in the development of other PARP inhibitor trials and obviously the biggest update so far is the FDA approval of olaparib and rucaparib in the US. Also the positive recommendation of the EMA CHMP for olaparib in Europe for patients with BRCA1 and BRCA2 alterations which suggests that probably we’re going to be seeing the drug approved in Europe in the next few months.
Also at ESMO there were some interesting abstracts being presented in prostate cancer. For example, Professor James provided a very interesting update in the long-term data for abiraterone as a treatment for metastatic hormone naïve prostate cancer from STAMPEDE. It was very reassuring to see the long-term benefit of adding abiraterone to ADT in those patients. Then there were also a couple of presentations of phase I trials of new drugs, one being an oral tubulin inhibitor that may be an alternative to taxanes in the future. The other very interesting, a new drug using the BiTE technology, a dual antibody targeting proteins of the prostate cancer such as PSMA and introducing drugs that will induce an immune response. These are very early days for these compounds but it’s very interesting to see this data on what can be the next generation of drugs for prostate cancer.
