PARP inhibitors are a family of drugs already in use in ovarian and breast cancer, also in some indications for pancreatic cancer, basically for patients who harbour deleterious mutations in their BRCA1 and BRCA2 genes. In prostate cancer a few years ago, we and others identified that there is a significant proportion of patients, maybe around 10% of patients, with advanced prostate cancer that also have either germline or somatic defects in BRCA1 and particularly in BRCA2. BRCA2 are the majority of cases. But also we identified that there is an additional 10-15% of patients with advanced prostate cancer that have mutations in other genes that are not BRCA1 and BRCA2 but have similar functions. Hence we thought that it was worth it to explore if these drugs could make a difference for prostate cancer patients.
There have been several trials over the last few years leading to a registration randomised phase III trial that had demonstrated that in patients with mutations in certain genes, and in this trial the cohort pulled together patients with BRCA1, BRCA2 and ATM mutations, there was a significant improvement in rPFS and also we know now that there is an improvement in overall survival for these patients when using olaparib rather than sequencing to a second hormonal agent after progression to abiraterone and enzalutamide. So we hope that this family of drugs is going to be part of the standard armamentarium for therapies in advanced prostate cancer although only for a subset of patients that are those that have particular gene alterations. This is probably the biggest difference in the field of prostate cancer right now: this is the first drug that is being approved on the basis of a molecular biomarker in prostate cancer.
What work involving PARP inhibitors have you been involved in?
Over the last few years I’ve been involved in the development of these early trials of PARP inhibitors after the initial genomic studies identifying a subset of patients harbouring DNA repair defects. We have reported on how often these defects are actually inherited and in the germline DNA, hence are not only relevant for the patient but may be potentially relevant for other members of the family who may deserve specific screening or more intense screening for cancer. We demonstrated that these drugs work in a subset of patients and we actually also elucidated how the tumour becomes resistant afterwards to the drug by developing secondary mutations which is interesting because the same DNA repair defect that makes the tumour sensitive to the drug also allows the tumour to be more plastic and evolve rapidly and develop these secondary mutations.
So, after the trial proving the efficacy of these drugs we are now focussing our work in trying to refine the patient selection strategy. With PROfound we have moved the field of prostate cancer into stratified medicine and this is a great advance but now further work is needed to actually be more precise and understand the patient to patient differences in response between patients that have mutations in different genes but even, we think, patients that may have a mutation in a similar gene and have very different outcomes. We think that we have to move from single biomarkers, single gene biomarkers, to more complex biomarkers that take into account the genomic background of the patient – mutations in other genes and other pathways and other factors that are relevant for the adaptation of the tumours to these agents.
How effective have these agents been in treating mCRPC?
We are now confident in saying that there is a subset of patients who are really sensitive to these agents. There is a group of patients, particularly those with BRCA2 mutations, that may derive important benefit and some responses are lasting for over a year in patients that have already received several lines of therapy. So this is clinically significant.
But still we can see that there are some patients, even with the canonical BRCA2 mutations, progress after six or seven months of therapy so we need to do better for them. On top of that there are these other patients with mutations in other genes that seem to report some activity but clearly the responses are not as common, neither as profound, as in the patients with BRCA2. So in order to deliver also benefit for these patients we are working in combining PARP inhibitors with other agents. This may be other agents that are already being used for prostate cancer, for example abiraterone and enzalutamide, and there are several trials exploring these combinations and whether these combinations can bring PARP inhibitors to a wider target population. But also in my group we are very interested in combining PARP inhibitors with drugs that are targeting other nodes in the DNA repair machinery. Because we think that that way we may bring additional benefit to those patients that may have mutations in some genes that confer not as much sensitivity as in the BRCA population but by giving them this extra help of hitting in another node the combination may be synergistic and bring significant responses for these patients.
How do you see this field progressing in the future?
I think that the field of incorporating genomics into patient stratification for prostate cancer is going to bloom in the next few years and we’re just starting to scratch the surface of what we can do. We have to be prudent; I think that one of the scenes of precision medicine has been to be extra-optimistic about what we can deliver. Unfortunately we know that these are patients with very advanced disease and when you give targeted agents there is always the risk that the tumour will adapt. The more targeted you are, the easier it is for the tumour to overcome the effect of the drug. But I think that we are going to see more patients being tested in order to identify patients who may benefit from PARP inhibitors. That is actually also going to take us as a side effect to other alterations being identified that I hope will accelerate the development of further drugs for prostate cancer patients.
When it comes to the field of PARP inhibitors in particular, I think that in two years, two to three years, we are going to have several trials reading out, testing different strategies for combinations. As I said, this may be combinations with the standard of care, AR targeting agents, but there are also trials in the pipeline combining PARP inhibitors with immune therapies or with other DNA repair targeting agents. This may help us to identify other populations that may benefit from PARP inhibitors among the prostate cancer patients.
Is there anything else that you would like to add?
This is a very exciting field to work on. Over the last ten years we have made great progress for patients with prostate cancer with the introduction of abiraterone, enzalutamide, now radium and many other drugs such as cabazitaxel and now PARP inhibitors. PARP inhibitors have been already approved in the US by the FDA, both olaparib and rucaparib, and we are expecting the European agencies to provide feedback towards the end of this year. But clearly there is still an unmet need for these patients; unfortunately men continue to die from advanced prostate cancer. Hence, this is not the final step but only the beginning of a new therapeutic approach being developed for these patients that we hope to continue evolving over the next few years, to do better for our patients.