Role of PARP Inhibitors Developing in mCRPC

Prostate Cancer

PARP inhibitors are beginning to show promise for patients with metastatic castration-resistant prostate cancer (mCRPC).

In January 2016, the FDA granted olaparib (Lynparza) a breakthrough therapy designation as a treatment for patients with BRCA1/2 or ATM-mutated mCRPC who have received prior taxane-based chemotherapy and at least either enzalutamide (Xtandi) or abiraterone acetate (Zytiga). The decision is based on findings from the phase II TOPARP-A trial, which demonstrated that olaparib had a nearly 90% overall response rate in a subgroup of patients who had DNA-repair defects.

Additionally, there is an ongoing phase III trial (NCT02987543) investigating olaparib versus enzalutamide or abiraterone acetate in patients with mCRPC who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations.

Approximately 340 patients will be randomized 2:1 to either the olaparib arm or the enzalutamide/abiraterone arm, respectively. The primary results of this study are expected to be seen in 2020.

OncLive: What is the excitement with PARP inhibitors in prostate cancer?

In an interview with OncLive, Alicia Morgan, MD, internal medicine, Mather Hospital, discusses the role of PARP inhibitors as a novel treatment strategy for patients with mCRPC.Morgan: There are a few reasons that we are excited about PARP inhibitors in prostate cancer. The first is that PARP inhibitors have been doing great things in other solid tumors. The prostate cancer community did not necessarily realize how big of a potential role there was for PARP inhibitors in prostate cancer. It is exciting to find a new direction for this group of patients.

Can you discuss the data that has been shown with PARP inhibitors?

What advice do you have for community oncologists who are interested in using PARP inhibitors for their patients?

Besides that, these medicines are well tolerated and patients can take it by mouth, so we do not need to use infusions to do these treatments. The idea of a targeted treatment in prostate cancer, besides targeting the androgen receptor, is an exciting thing as well. For patients and providers, we have become excited for very good reasons. For men who have DNA-repair defects, such as PALB2 or ATM in addition to BRCA1/2, we can see that there is a better response rate in terms of prostate-specific antigen (PSA) response and progression-free survival (PFS), and we expect that this is going to translate to overall survival for men with these defects. There is a lot of excitement about whether men need to have these defects to respond to PARP inhibitors. We think that they most likely do, but for that selected population, these targeted agents seem to improve these meaningful clinical outcomes. I would advise medical oncologists and urologists to think strongly about getting genomic and genetic sequencing data for their patients as they are approaching a time when they might think about using PARP inhibitors. For most community oncologists, this is going to be after they have used FDA-approved agents for mCRPC, such as enzalutamide, abiraterone, and chemotherapy, as well as our other therapies, such as immunotherapies and pharmaceutical options.

If you can get the genomic and genetic sequencing data at that point, you might be able to get off-label PARP inhibitors. We have had some good luck with that clinically. You also might be able to advise your patients to go to a clinical trial at an academic center to get more data with PARP inhibitors.

Can you discuss combinations with PARP inhibitors?

One of the challenges that we are seeing for men with prostate cancer is there are so many trials available with PARP inhibitors that there is a concern that we may have too many trials and not enough patients. I would strongly encourage urologists and medical oncologists with any interest in this to identify their patients. For those patients who are able to enroll, the oncologists could try to get them to clinical trials to help build the data to move this field forward.PARP inhibitors are being looked at in many ways, such as with androgen receptor—directed therapies, immunotherapy approaches, and radiation approaches. There is interest in understanding whether there may be a synergistic action with platinum agents because there is some evidence that patients who have DNA-repair defects may be more sensitive to agents such as carboplatin rather than the traditional chemotherapy docetaxel.

How do you determine who should receive a PARP inhibitor?

These approaches in combination are exciting. We do think that these agents may be synergistic with PARP and hopefully combinations will be coming soon. Usually we use genetic and genomic testing to determine who should receive a PARP inhibitor. In the community and in practices, as they are evolving over time in academics, this has been less standardized than it should be. Many people are getting testing on the somatic mutations within tumors. To be most effective, we could also check the individual’s genetic germline mutations. It is the double hit that we think is going to have the most impact and be most predictive in terms of being responsive to a PARP inhibitor.

What is the potential of olaparib in the mCRPC population?

Both genetic and genomic mutations are important. If you can only do one or the other, one can start there but I try to get both of those when I am determining who should get PARP inhibitors. Olaparib is the PARP inhibitor for which we have the most data right now. It was studied in the TOPARP-A study by Dr Johann de Bono’s group. It was published a few years ago and there are ongoing studies with olaparib in combination.

In that study, patients were selected to be included as long as they had undergone multiple prior therapies and were refractory to treatment. They underwent biopsies before being treated with olaparib and then were followed. They were assessed for PSA response and for PFS. In the study, for patients who had DNA-repair defects, their response rate was around 88%, based mostly on PSA response. That is a high response rate, which is very exciting. It was higher than what we would expect in a regular clinical trial and there was not randomization. This was a single-arm study.

Is there anything else you would like to add regarding PARP inhibitors?

Patients who did not have DNA-repair defects did not seem to respond in that way. All of the patients who had BRCA2 mutations did appear to respond. Olaparib in prostate cancer is far along in its development and initiation into further clinical trials. The other PARP inhibitors are on their way.PARP inhibitors are an exciting and fascinating targeted type of therapy in prostate cancer. As clinicians, both medical oncologists and urologists, we need to be thoughtful about who is receiving these drugs. They do have some toxicities—they can make people tired, and they have other effects on bone marrow suppression.

Any treatment that we use, especially a targeted treatment, we should try to target the right population to understand that population more clearly and thoroughly. Using these agents in those who we think will respond can go a long way toward improving outcomes in patients with prostate cancer.