At the end of September, initial results of the PROFOUND trial were published. This is the first trial ever to prove the effectiveness of a precision medicine for prostate cancer. The trial shows that PARP inhibitors like olaparib, drugs that target the cell’s DNA damage repair machinery, are effective in men with metastatic, hormone resistant prostate cancer who have a mutation in one of the BRCA or ATM genes.
The next step is to ensure this research makes its way into practice and the treatment becomes available to patients. Alongside clinicians and men we will do all we can to ensure this treatment is available as quickly as possible.
Short term: Regulatory approval, cost-effectiveness assessment and companion diagnostics
The first step will be regulatory approval, establishing that the medicine is safe and effective. After regulatory approval, the treatment should be available privately. NICE will then begin its cost-effectiveness assessment and we will be working with NICE, NHS England and the manufacturer to understand and overcome any questions or barriers to olaparib’s availability on the NHS.
Olaparib will face some challenges which are shared with other precision treatments. The first is the small patient population, with the medicine costing the same amount to create as a treatment for a larger population of patients, it will likely have a higher cost which could be a barrier for it being available on the NHS. The second challenge is the diagnostic used to identify men with cancer cells that BRCA or ATM gene mutations. NHS England is still developing a system for commissioning these diagnostic tests. This is complicated further because the test requires somatic testing (the cancer cell’s genes) rather than germline testing (the man’s genes).
There is a great will, shared by NHS England, charities, pharmaceutical companies and patients to see these issues resolved. We’re already engaging with NHS England to explore how the diagnostic tests can be commissioned.
This could make a huge difference for men with advanced prostate cancer by giving them a brand new option for treatment.
Medium term: Treatment earlier in the cancer pathway
As mentioned, PROFOUND isn’t the only clinical trial into olaparib for men with prostate cancer. Dr Mateo, who completed his Prostate Cancer UK and Movember funded Clinical Training Fellowship at the Institute of Cancer Research in London, told us, “As part of my Fellowship, I also wanted to understand when spontaneous BRCA mutations occurred. This is important to work out how early in a man’s prostate cancer pathway olaparib treatment might benefit him. We still don’t know whether the mutation is present in the very first cancer cell, but we do know from looking in the first diagnostic biopsies of men who later went on to develop metastatic prostate cancer, that these mutations are already present at the point the cancer becomes clinically significant. This opens the door to seeing whether olaparib might benefit men with BRCA gene mutations earlier on in their treatment pathway. The next wave of clinical trials with drugs like olaparib are already testing this possibility.”
Long term: Combination therapies
Finally, when scientists first thought about how drugs like olaparib that target DNA damage repair machinery might be useful, they didn’t initially plan for it to only work in people with a BRCA mutation. Instead they thought it might be a drug that could make other treatments, like radiotherapy or chemotherapy, work better. This is because olaparib works by blocking one of two ways that a cell can repair broken DNA. Mutations in BRCA, ATM and other DNA damage repair genes block the second pathway. When men with a BRCA mutation take olaparib, their cancer cells can no longer repair breaks in their DNA and the cells die.
“It’s a bit like a table with a leg missing,”, says Dr Mateo. “With just three legs the table will stay standing, even if it’s a bit unstable. If we take out another leg, the table collapses.”
Men whose cancers don’t have a DNA damage repair mutation can still repair the DNA after olaparib treatment via the cell’s other repair pathway, which is why this drug doesn’t work for them when it’s given on its own. But treatments like radiotherapy and chemotherapy work by introducing additional DNA breaks and overwhelming the cell’s repair mechanisms. It’s possible that the two treatments together might have an even greater effect than either one alone.
The big question here though will be about side effects, especially in the case of chemotherapy and olaparib, both treatments affect the whole body. This means that while tolerable on their own, side effects of the combined treatment might be too severe. On the other hand, radiotherapy may offer greater potential for combination therapies, because it can be better targeted to the cancer, especially as new trials are now looking at even targeting radiotherapy to tumour metastases outside the prostate.
Recent research has also shown that drugs like olaparib can boost the body’s immune response to cancer, suggesting that combining olaparib with immunotherapies may be another way to increase the number of men who can benefit from this treatment.
Understanding and defining how different treatment combinations might enhance the effect of olaparib or allow more men to benefit from this new treatment are really important, but it’s likely to be a few more years before we have any definite answers about when to give what treatment combination to which man to ensure the best possible outcome.