This paper was written with two of my mentors, Adrienne Chen and Kinjal Parikh, who are both oncology pharmacists. We wanted to talk about the initial FDA breakthrough therapy designation of olaparib that happened back in 2016 and provide the reason why PARP inhibitors would work in prostate cancer potentially and also go through our clinical experience and the pharmacology of PARP inhibitors for prostate cancer.
Metastatic castration resistant prostate cancer is a disease that has limited treatments and limited targeted treatments especially. We know that in patients who have a BRCA mutation or certain other deleterious gene recombination deficiency mutations those patients have more aggressive disease and they are less likely to respond for a longer period of time with our traditional agents used for prostate cancer. So it’s really important that we find targeted ways to help those patients so that we can target those mutations that they already have acquired.
How do PARP inhibitors work?
Damage happens to DNA all the time and we know that there are multiple mechanisms to repair DNA. One of those is homologous recombination repair and that is one of the things that is inhibited by genetic alterations like BRCA or ATM mutations. Another way that DNA is repaired is through PARP and PARP is a family of enzymes that repair single strand DNA breaks. So when a patient just has a BRCA mutation they are able to repair their DNA using these other mechanisms. However, if you combine one of those deficiencies in DNA repair with a PARP inhibitor then you’re blocking two mechanisms of DNA repair leading to DNA strand breaks and ultimately cell death of those cancer cells. It’s an idea that’s called synthetic lethality.
How effective is olaparib for metastatic castration-resistant prostate cancer?
The phase II study TOPARP-A showed really promising results of olaparib in prostate cancer and that was the study that had come out when we wrote the original article on olaparib in metastatic castration resistant prostate cancer. But now we also have the PROfound study which is a phase III study that included far more patients and showed that in patients who had a BRCA1, BRCA2 or ATM mutation, those patients were in cohort A, and those patients had the best response to PARP inhibitors.
When they looked at overall survival data they did not see a statistically significant difference from what has been presented so far. However, they did allow patients to cross over who were in the control arm into the olaparib arm and 80% of patients actually did cross over. So I don’t know that we will see a difference when more data comes out, when that data matures, I would not be surprised if we don’t. But the initial results are very promising.
Have there been any recent developments in this area?
Yes, May 2020 was a really big month for PARP inhibitors in prostate cancer. We actually moved from having breakthrough therapy designation to actual FDA approvals. So olaparib receives an FDA approval for germline or somatic homologous recombination repair gene mutated prostate cancer in patients who had received a prior therapy like enzalutamide or abiraterone and had progression following one of those agents. We also saw an FDA approval for rucaparib and this was an accelerated approval based on the TRITON2 study. So very exciting things are happening now with prostate cancer and PARP inhibitors.
What is your own clinical experience of using PARP inhibitors to treat these patients?
I’ve had several patients receive PARP inhibitors for prostate cancer. Regarding the adverse effects that they experience, they’re generally well tolerated. The main things that I hear from patients are fatigue and sometimes some nausea. The fatigue is something that usually sticks around but the nausea does seem to improve over time. So in my patients who initially have nausea up front, as they’re on it for more months it tends to lessen or no longer require anti-emetic use. So those are the most common side effects. We also sometimes see anaemia but in my practice with prostate cancer I haven’t seen any required dose reductions based on anaemia in this select patient population.
Now, one thing that we’ve struggled with is getting insurance approval for olaparib in prostate cancer but now I’m really hopeful with these FDA indications that we’ll actually be able to get insurance approval. So this is really exciting to have those indications and be able to help more patients. We’ve been fortunate to be able to use the manufacturer programmes to help patients receive medications through medication assistance. So we have had several patients receive them but I’m hopeful that we can expand this even further now so that more patients can benefit from these therapies.
How do you see the use of PARP inhibitors for prostate cancer developing in the future?
I think there are so many possibilities for PARP inhibitors for prostate cancer. One thing that is currently being looked at and will continue to be coming in more studies is looking at combination therapies. So we know that we can add different therapies to hit different targets to potentially prolong responses in our patients. So we’re looking at PARP inhibitors plus abiraterone or enzalutamide, PAR inhibitors plus immunotherapy where there’s checkpoint inhibitors, and potentially PARP inhibitors with anti-angiogenesis inhibitors. So because these types of treatments have different toxicity profiles they don’t have the cumulative side effects that we might see if we added a PARP inhibitor with chemotherapy. That potentially could be more toxic than a patient is able to tolerate so I’m really excited about these other combination therapies.
PARP inhibitors have been shown to also improve the PD-L1 expression in patients who have these DNA repair deficiencies so it will be interesting to see if patients might be able to respond to things like immunotherapy that previously were not able to respond to those therapies.
I think that other future directions would be moving this up earlier in the line of treatment so if we know a patient has a deficiency in DNA repair would we be able to move up a PARP inhibitor to an earlier line of therapy for them when they have metastatic castration resistant prostate cancer. Perhaps we would use PARP inhibitors for patients who have more localised disease, that’s something that is being evaluated as neoadjuvant therapy for patients who are going to be going to surgery if they have one of these DNA deficiencies. That’s also a really interesting thing to consider and it will be exciting to see what those results show.
