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Getting precision treatments over the line will be a team effort, not an individual bolt for glory

Published on 07/12/17 at 10:46am

We’ve finally reached the starter’s block when it comes to precision medicine approaches to prostate cancer, but Dr Matthew Hobbs, Deputy Director of Research at Prostate Cancer UK, argues that getting over the finish line will require clear collaboration and teamwork between research funders, academic researchers and industry partners.

No matter how many times we hear ‘it’s something you die with, not from’, there’s no getting away from the fact that for nearly 12,000 men per year in the UK, that’s untrue. Prostate cancer is a killer, and GLOBOCAN projections predict that not only will this continue, but that year on year more men will die. By 2025, they predict that the number deaths from advanced prostate cancer will exceed 14,500.

However, we believe that there is light at the end of this particular tunnel. And for men with advanced prostate cancer, that light may be precision medicine. It’s the conference buzzword of the year, and it seems that everyone from Dame Sally Davies to James P Sullivan can agree that identifying the molecular change driving a person’s cancer, and treating that change, is one of the most important ways that we can make a lasting and noticeable impact on cancer survival. 

Yet there are going to be challenges for all of us in adopting this approach. For pharmaceutical companies, it may require new pricing models and adapted strategies to get through NICE/SMC appraisal as potential patient population sizes drop. On the other hand, this may be mitigated by other factors such as increased overall survival (and therefore increased time on each treatment), increased effectiveness, and perhaps also a wider move towards ‘pan-cancer’ therapies based on a shared molecular driver rather than a specific disease location. As overall survival increases though, it may also add urgency to the need for surrogate end points for clinical trials in order to minimise the time it takes to get the evidence needed to bring a new drug to market.

For us, as prostate cancer-specific research funders, the challenges are mainly scientific. We’ve already overcome numerous hurdles to reach the point where we can start to invest in precision approaches to prostate cancer, most significantly the historic lack of funding for prostate cancer research. This was in part due to scientific limitations: the prostate is a tremendously difficult tissue to image and access, and our inability to distinguish aggressive from indolent cancers was an additional major handicap. In addition, men’s reluctance to openly discuss health issues and indeed even to engage with healthcare professionals meant lower awareness of the disease, and less urgency around calls for increased funding. The good news is that in recent years we’ve gone some way towards closing the funding gap, and have made huge strides in increasing awareness and empowering men to take charge of their health.  

Now, our challenges are predominantly around how to identify the molecular changes driving the disease at every stage, and then to match this to an appropriate treatment.

Some of this work is already underway. We’ve seen particularly impressive momentum in the most advanced disease setting, where men have become resistant to all standard treatments. This research culminated in two game-changing publications. The first, produced by an international consortium, defined for the first time the mutational landscape of metastatic castration-resistant prostate cancer (mCRPC). Approximately 90% of the tumours they sequenced harboured at least one actionable mutation. These driver mutations covered a number of different genes but could be grouped as follows:

  • Androgen receptor signalling pathway aberrations
  • Alterations in the PI3K pathway
  • Alterations in the WNT pathway
  • Changes affecting cell cycle pathways including RB1 loss
  • Changes in genes playing a role in DNA damage repair (both somatic and germline mutations)

The second major leap forward was by a Prostate Cancer UK-funded team at the Institute of Cancer Research in London, who ran a series of clinical trials to demonstrate that men with genomic aberrations that interfere with DNA damage repair respond well to Olaparib. This is a PARP inhibitor owned by Astrazeneca that has previously been used to treat BRCA-mutated ovarian cancers. It is also the first ever molecularly targeted treatment for prostate cancer.

However, we don’t yet know how many of these driver mutations exist in an earlier disease setting, where targeted treatment could arguably prove even more impactful. To attempt to answer this question, we have just announced the first award in the Prostate Cancer UK Precision Medicine Programme. Eventually, we believe that a series of parallel trials in different disease settings will be needed, but our first investment, made with part-funding from The Movember Foundation and The Distinguished Gentlemen’s Ride, concentrates on hormone-sensitive metastatic disease. This research programme seeks to combine our enhanced understanding of molecular drivers with the clinical trial platform established by STAMPEDE in the UK to identify and test biomarker-treatment pairings.

At this stage of the disease, there are likely to be fewer disease drivers than in the later setting. This is because men will have been exposed to fewer treatments, which in turn should mean less clonal evolution, and so fewer disease-driving mutations. But if we can find and target those driving mutations that do exist at this stage of the disease, survival gains may well be measured in years rather than months.

In the long term, we anticipate making a series of investments in this and other disease states to once and for all do away with the ineffective one-size-fits-all approach to prostate cancer treatment that is still the default today. This is likely to include a trial platform in metastatic castration-resistant prostate cancer, which will give quicker and more obvious read outs on the activity of targeted treatments. This in turn will allow the most successful biomarker-treatment pairings to be quickly accelerated into trials in earlier disease states. At the other end of the disease spectrum, investment in a precision medicine approach to high-risk, localised disease could mean streamlining and intensifying treatment for men with high-risk disease, driving down recurrence and deaths from recurrent conditions. At the same time, this is also likely to result in clearer stratification of genuinely ‘low risk’ men who could then avoid unnecessary treatments.

While we’re confident that this is the future of prostate cancer treatment, we also know that we won’t succeed in making precision medicine the norm without support and buy-in from industry partners. We face challenges attaining this ideal, but I believe our shared goal of better treatment for patients means that none of these are challenges we can’t overcome together.

Most obviously in this case we, and the academics leading these major multi-arm multi-stage trials, need to engage with industry partners to build up the arsenal of treatments we have available to target the various driver mutations at play. Many of these drugs will already be in clinical development for other cancers, or at least well along the pathway to clinical development.

Partnership and knowledge exchange between the charity and industry partners will be crucial to almost all aspects of our research strategy. There will be times when our motivations, and approaches to getting treatments across the line, will vary, but in the end the pay-off from getting effective, targeted treatments to men at the time when they can benefit most significantly from them, will mean we all win. 

At Prostate Cancer UK, we’re developing an approach to working with pharmaceutical and medtech companies that would mean we can work together to achieve shared goals transparently and independently. We would very much like to open communications with industry partners who could help us inform that work. In addition, we’d love to hear from any companies prepared to share information about their pipeline, and how their clinical and pre-clinical assets may be relevant to improving treatment for men with prostate cancer. We know that there are plenty of examples of good collaboration between industry and individual researchers. We believe that we can build on this to bring even greater mutual benefit and enhanced knowledge sharing at an organisational level.

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