The Role of PARP Inhibitors in Prostate Cancer

Video

A key opinion leader explains the role of PARP inhibitors in metastatic prostate cancer and reviews clinical trial data.

Matthew Fowler: The audience watching this is probably familiar with hearing about PARP inhibitors in ovarian cancer, but what’s the role of PARP inhibitors in prostate cancer?

Oliver Sartor, MD: We have 2 FDA approvals. Let’s start with that. We have 2 agents: first an accelerated approval, rucaparib; second, olaparib, which is a full approval. The indication is a little different. I mentioned the homologous recombination repair panel that is applicable to the olaparib. Yes, you’ve got BRCA1 and BRCA2, but you also have a series of other genes, including PALB2, that can be indications for the treatment.

We don’t have a huge amount of data individually outside the BRCA1 and BRCA2. Some of the data are a little iffy. For instance, the ATM is a little controversial, and CDK12 is a little controversial. Nevertheless, we do have the FDA approval for olaparib within this panel of homologous recombination repair genes. By the way, it doesn’t have to be somatic. It turns out that the germline BRCA1 and BRCA2 can also apply.

When we look at the rucaparib, the panel of genes is restricted to BRCA1 and BRCA2. By the way, we have circulating tumor DNA in addition to tissue available for BRCA1 and BRCA2 and the addition of ATM on the olaparib side. We have circulating tumor DNA, and we have tissue-based next-generation sequencing [NGS]. We have different panels of genes and different requirements for pretreatment. All must be metastatic castration-resistant prostate cancer. If you look at the olaparib label, it would follow in sequence behind 1 of the novel hormones—1 of the abiraterone-, enzalutamide-, and apalutamide-type agents. If you look for the rucaparib, it comes after the novel hormones: the abiraterone and enzalutamide but also a taxane.

Of course, you can come post-taxane as well with the olaparib, but the indications are a little different. We have germline considerations and circulating tumor DNA that we can consider, plus somatic alterations with NGS and treatment sequencing. For the patients themselves, many times, these individuals may have pancytopenia from prior treatments or significant problems with their blood counts, and that’s a relative contraindication. The PARP inhibitors are going to have an effect on the amount of...cells in a certain portion of patients. You must be very cautious when it comes to patients with significant anemia, thrombocytopenia, or neutropenia coming into the treatment. That has to be monitored very carefully and may even be a contraindication depending on how bad it is.

Matthew Fowler: There are a pair of studies that I want to get into a little, focusing on rucaparib and olaparib. Could you start with the TRITON2 study and review the design, the population, and some of the results that came out of that, focusing on rucaparib?

Oliver Sartor, MD: Sure. The TRITON2 study was a study that led to the FDA approval in an accelerated way for rucaparib. There were a variety of teams that focused on BRCA1 and BRCA2. The real parameter to watch was not the PSA [prostate-specific antigen] or time to PSA progression; it was the objective response rate as measured by radiographs, typically CT scans. The patients who had observable disease were treated with rucaparib; they typically were in that post–abiraterone-enzalutamide, postdocetaxel state, and looking at tumor shrinkage. Tumor shrinkage was achieved in a substantial proportion of patients with BRCA1 and BRCA2; that led to FDA approval. It was a little different from the typical phase 3 design. BRCA1, BRCA2, post–abiraterone-enzalutamide, post-taxane radiographic response are the key parameters for rucaparib.

Matthew Fowler: That second study that I alluded to was the PROfound study focusing on olaparib. Could you talk a little about that as well?

Oliver Sartor, MD: Sure. This was differently designed study, with the homologous recombination repair genes that I’ve mentioned repetitively at this point. These individuals had all progressed after abiraterone-enzalutamide and potentially had taxane or not; that was potentially a stratification factor. The randomization was to either the olaparib, or to a second-line hormone. If the patients had previously had abiraterone, they could be randomized to enzalutamide in the control arm. The primary end point was radiographic progression-free survival [rPFS]. That’s measured in a very specific way by the Prostate Cancer Working Group 2 and Group 3 criteria.

There are a series of metrics related to bone scans and how progression is measured in bone scans and radiographs and how progression is measured, which is basically RECIST-type criteria. These individuals were randomized for rPFS. There was a crossover at those individuals who did progress by rPFS, and they could be randomized initially through the control arm and then switch over to the olaparib. There were 2 New England Journal of Medicine papers for olaparib. One thing that was very important was reporting on the primary end point, rPFS. Secondarily, the overall survival data came out, and it was quite strong despite the crossover. There was a division in the olaparib to divide it into what we call cohort A and cohort B. The cohort A genes were BRCA1, BRCA2, and ATM; the cohort B genes were all the others. There were a whole different set of analyses related to cohort A and cohort B. But because of the commonalities and the robust nature of cohort A, those were the primary end points. There was this cohort A and B for the olaparib. The bottom line is, the FDA saw fit to include all the homologous recombination repair genes within the FDA approval.

Transcript edited for clarity.

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