PARP Inhibitors Hold Promise in mCRPC and Biallelic DNA Repair Gene Defects

Evan Ya-Wen Yu, MD

Recent data suggest that PARP inhibitors could be a beneficial treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) who express homologous recombination deficiency (HRD) or who have biallelic DNA repair gene defects, said Evan Y. Yu, MD.

The GALAHAD trial, a phase II study presented at the 2019 Genitourinary Cancers Symposium, evaluated the use of single-agent niraparib (Zejula) in patients with mCRPC and biallelic DNA repair gene defects. At a median follow-up of 5.7 months, the composite response rate was 65% in patients with biallelic BRCA1/2 mutations. Composite response rate is an endpoint taking into consideration factors like RECIST evaluation and prostate-specific antigen (PSA) decline. Among the 20 responders, duration of response exceeded 4 months in 13 patients and 6 months in 8 patients; 14 patients remain on treatment.¹

In the phase I KEYNOTE-365 study, another early clinical trial assessing the use of PARP inhibitors in this space, response rates were modest. Cohort A of the study looked at the combination of the PD-1 inhibitor pembrolizumab (Keytruda) plus olaparib (Lynparza) in docetaxel-pretreated patients. At a median follow-up of 11 months, the composite response rate in these patients was 15%.²

Yu, a professor of medicine at the University of Washington in the Seattle Cancer Care Alliance, said that the benefit of PARP inhibitors may extend beyond these specific molecularly selected subsets of patients. These are early data, but they suggest that treatment in the field of prostate cancer is moving toward a precision medicine approach.

OncLive: What were the biggest takeaways from KEYNOTE-365?

In an interview with OncLive, Yu highlighted 2 key studies with PARP inhibitors in mCRPC and discussed challenges that need to be addressed in this space in order to further progress.Yu: This is a study evaluating combinations in mCRPC with pembrolizumab plus several different treatment options. What I presented at the 2019 Genitourinary Cancers Symposium was [data from] Cohort A, [in which, investigators evaluated the combination of] pembrolizumab with olaparib in patients who previously received docetaxel. These patients had received up to 1 other line of chemotherapy, so they could have had docetaxel and cabazitaxel. They could have also received up to 2 hormonal therapies such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi). It was a pretty advanced patient population, as evidenced by the fact that 41% of patients had measurable visceral disease. The patients then received pembrolizumab at 200 mg every 3 weeks with olaparib at 400 mg.

What we saw was that the combination was pretty well tolerated—only about 15% of patients had immune-mediated adverse events, and these events were only grade 1 and 2. There were no grade 3 or 4 events observed. In regard to efficacy, we saw about half of the patients had some prostate-specific antigen (PSA) decline, but the confirmed PSA response rate was 12%. In regard to soft tissue disease, we saw that about 29% of patients had >30% shrinkage in soft tissue disease—I think this is impressive. The confirmed [overall] response rate, however, was 7%. We need to figure out what the discrepancy was between those who had shrinkage and the eventual ability to confirm it with a second imaging study.

What was the rationale for combining a checkpoint inhibitor with a PARP inhibitor?

Is there anything you would like to add about KEYNOTE-365?

You also presented the preliminary results of the GALAHAD study of niraparib in mCRPC. What were the key takeaways from this research?

In terms of molecular analysis, this was an unselected patient population. Whole exome sequencing was done in 17 patients who had soft tissue for analysis. We found 1 patient with a BRIP1 alteration. That being said, we did not definitively find HRD in any of the patients. Additional molecular analyses with sequencing on more patients with soft tissue disease is needed. We will also need to look at other factors like microsatellite instability and tumor mutational burden (TMB). This cohort is being expanded to 100 patients; these data [that were presented] involved 42 patients. A phase III trial is being launched in patients with mCRPC who received prior docetaxel and either abiraterone acetate or enzalutamide. They will be randomized to receive pembrolizumab plus olaparib versus the alternate hormone agent. For example, if you had abiraterone, you would get enzalutamide, and vice versa. Since this was an unselected trial, we did think there was a good chance we would find patients with HRD. There are data in breast and ovarian cancers showing that when you add a PARP inhibitor to patients with HRD, you increase PD-L1 expression and TMB. There is quite a bit of theory there and data to support it. In the HRD-proficient population, there even is growing literature in breast cancer for patients who do not have BRCA mutations that if you give them a PARP inhibitor you can increase PD-L1 expression. More recent publications show that because you are giving a PARP inhibitor and you have these unresolved DNA fragments that accumulate in the cytosol, you can induce type-1 interferon and lead to anti-tumor immunity. Following up with the PD-1/PD-L1 antibody makes a lot of sense there. It is an interesting study. Because it is a nonrandomized study, it is interestingly hypothesis-generating. Acquiring more patients, and understanding the demographics and molecular data, will help us move this treatment forward. Of course, the only way to prove this is beneficial in patients is to do the randomized control trial, which is being launched.GALAHAD is using niraparib, which is another PARP inhibitor, in this setting. So far, there are no data to suggest that one PARP is better than the other. Some have more enzymatic activity, others have better PARP-tracking capability, but we don't know if one is generally better than the other. At this point, there are multiple PARP inhibitors being studied, with niraparib being one of them. This trial was a very interesting and educational one in the fact that when it first started, they used a circulating tumor DNA assay and accrued patients very rapidly. As time goes on, however, I think it makes sense to focus on patients with biallelic alterations.

How rare are these biallelic gene defects?

That being said, the results on patients with biallelic alterations—about 50 patients—looks pretty promising. We are seeing good composite response rates, and the only reason I am focusing on this is because it focuses on RECIST evaluation, PSA decline, and circulation tumor cell enumeration. Again, these are open-label phase II nonrandomized trials, but they certainly look promising. If you look at the Stand Up to Cancer studies, it was found that about 23% of patients harbored biallelic alterations in DNA repair genes. That being said, as time moves forward, we may find that those rates are not quite that high. It might be lower than that because we are at tertiary cancer centers and we may be seeing a different patient population. Do I think it is a significant rate? Yes. Do I think it is ultimately going to be as high as 23%? Maybe, on the lower side.

How do both of these studies support a precision medicine approach in prostate cancer?

Colin C. Pritchard, MD, PhD, from our center, published data looking at germline mutations and found that that rate was 11.8% in patients with metastatic prostate cancer, notwithstanding whether they were castration-resistant or hormone-sensitive. I think those are pretty interesting data, and if they hold true, one could argue that we might be talking about needing to screen everybody with metastatic prostate cancer, not just for the therapeutic options but also for downstream cascade testing and family testing. Precision medicine is ultimately the way to go. If we are smart enough to understand the biology and know that it predisposes a certain response to a certain class of agents, we ought to do it. Now, the challenge is figuring out how to do it and how to standardize it. You ask a really great question, because as we look at all these studies with PARP inhibitors, researchers want to compare. You said this 1 study had an 88% response rate, well GALAHAD had a little bit less than 70%. It could easily be the assay. The assay is an issue. For instance, we are mandating in GALAHAD biallelic alterations, but in a study like TRITON2, that was not mandated. Decisions are being made based on this. It looks like with BRCA1/2 and high penetrants, you are going to have it early and a second allele lost later. With some of these other genes, they might not have the same level of penetrance. If your assay is not detecting everything you need to detect, you might be doing it wrong. I have concerns over saying we should drop ATM mutations.

What is your take-home message regarding the use of PARP inhibitors in prostate cancer?

There is this thought that ATM-altered patients do not respond as well to PARP inhibitors and there is some growing literature in that area. However, a lot of that literature is from patients who we cannot say for sure if they had biallelic ATM because the penetrance is not as high. You could have had a germline ATM alteration—it could be in the tumor and you think it is a driver, but maybe the second allele was not even lost. Now you are saying that PARP inhibitors do not work in ATM-positive patients, which is an incorrect statement. These are the challenges we face. I am totally on board with precision medicine. I know it is where we need to go, but we need to find ways to slow ourselves down and do it the right way. It is not about rushing to the finish line and developing drugs; we have to do the right assays. I feel strongly that in patients with true HRD and biallelic alterations in some of these repair genes, we will see success with the PARP inhibitors. Assay development is going to be very critical. The next question is: Are we going to find indications for molecularly unselected patients for PARP inhibitors? Moving forward, we have to also be mindful of the fact that we still are not curing these patients. They are developing resistance to these drugs and we have to figure out the mechanisms.

References

1. Smith MR, Sandhu SK, Kelly WK, et al. Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of GALAHAD. J Clin Oncol. 2019;37(suppl; abstr 202).
2. Yu EY. Massard C, Retz M, et al. Keynote-365 cohort a: pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(suppl; abstr 145).

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