POLO Trial Underscores Need for Screening in Metastatic Pancreatic Cancer

Donald A. Richards, MD, PhD

The POLO trial demonstrated that maintenance therapy with a PARP inhibitor can be beneficial for patients with BRCA-positive metastatic pancreatic cancer, thus underscoring the need to screen these patients for molecular abnormalities so that they can be paired with the most effective treatment possible, said Donald A. Richards, MD, PhD.

Specifically, results from the randomized phase III trial showed that maintenance therapy with olaparib (Lynparza) was found to significantly improve progression-free survival (PFS) versus placebo in patients with germline BRCA-positive metastatic pancreatic cancer.^1,2

The median PFS observed with the PARP inhibitor was 7.4 months versus 3.8 months with placebo (HR, 0.53; 95% CI, 0.35-0.82; P = .0038). Furthermore, 22.1% of patients who received olaparib had no disease progression after 2 years compared with 9.6% of those who were given placebo.

Although an interim analysis of overall survival (OS) failed to show a difference between arms (18.9 months vs 18.1 months; HR, 0.91; 95% CI, 0.56-1.46; P = .68), investigators are waiting for the data to mature to determine whether there will be a difference in the curves.

“It's important to look for these germline mutations,” said Richards. “I believe that the use of a PARP inhibitor as a maintenance therapy is a wonderful idea for those patients; the quality of life is going to be preserved and the time spent off chemotherapy is a major benefit.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Precision Medicine, Richards, a medical oncologist at Texas Oncology, highlighted the key takeaways from the pivotal POLO trial and underscored the importance of genetic testing in metastatic pancreatic cancer.

OncLive: Could you discuss the POLO trial with olaparib and the key takeaways from this research?

Richards: The results of the POLO trial were presented at the 2019 ASCO Annual Meeting and were also was published simultaneously in the New England Journal of Medicine. This is a trial examining olaparib, a PARP inhibitor, as maintenance in patients with metastatic pancreatic cancer who have a BRCA1/2 mutation. Investigators had to screen over 3300 patients to identify about 250 patients, which was a large process—a major undertaking.

Those patients were able to go on the study if they had received at least 4 months of a platinum-containing regimen. Once they had completed those 4 months, if they had stable disease or a partial remission, they were then eligible to receive maintenance therapy with olaparib. The PARP inhibitor was given 300 mg twice daily. It was a 3:2 randomization and they ultimately randomized about 150 patients. Their primary objective was PFS and they noted a major difference in PFS of 7.9 versus 3.8 months—a clear difference in the curves. As such, it was a very positive trial.

Among the secondary objectives of the trial was OS. The OS data did not look particularly different [between the arms], but they are immature. As such, investigators will re-evaluate OS at full maturity and we'll wait to see if there is a benefit [with olaparib]. Some of the other secondary endpoints of the trial included response rate and time to second progression. Response rate was fairly significant in the patients who received olaparib, and some of those responses were quite durable. A fairly significant number of patients were progression-free at almost 24 months as well, so it's a game-changer.

[These results] indicate a need to screen our patients with pancreatic cancer for these BRCA mutations. [We do not see] an improvement in OS yet, but PFS is a very significant endpoint. The alternative is continued systemic chemotherapy. I believe that the study also showed that the quality of life of these patients was not hampered with olaparib. There were a few more adverse events in the olaparib arm—greater fatigue and more anemia—but overall, [the agent was] very well tolerated.

When can we expect updated data?

They need 106 events to occur. [The results presented at the 2019 ASCO Annual Meeting] were at 46% maturity for OS, so they're going to wait until about 67%. I estimate it's probably going to be at least another year or 18 months before we'll see the final OS data.

Could you expand on the role of PARP inhibitors in pancreatic cancer and how they tie into this shift toward precision medicine?

We know that if patients have a BRCA mutation, they have problems with DNA repair. They are unable to repair double-strand breaks. PARP inhibitors increase the number of single-strand breaks. When a patient has a BRCA mutation, those lethal mutations then accumulate. A normal cell without a BRCA mutation can repair itself. Dual inhibition in DNA repair leads to cell death.

There are other PARP inhibitors that are being investigated. The other exciting thing is that while only [a certain percentage] of the patients with metastatic pancreatic cancer had germline mutations, there are other mutations that may be vulnerable. For example, somatic mutations do occur in pancreatic cancer, and patients with those mutations may benefit from these drugs. There are a few reports out there of patients with somatic mutations who have had a benefit with PARP inhibition. There are also other mutations, such as PALB2 and ATM that may also benefit from this [approach] that are being evaluated in future studies.

What does the testing for these mutations currently look like?

The National Comprehensive Cancer Network guidelines recommend to go ahead and test patients with advanced metastatic pancreatic cancer for BRCA1/2 mutations. As such, that's becoming widely accepted. However, the role of testing somatic mutations is still under consideration. We are doing that. We are looking for those heels of vulnerability. Some of the issues [with making testing more widespread] include the availability of tissue and the cost of the tests; however, costs have come down [over the years].

Where should future research focus?

We need to figure out a way to target the KRAS mutations; they’re prevalent in pancreatic cancer. Some new agents are able to start targeting certain KRAS mutations, but it's not a very druggable target right now. However, I know that work is proceeding in that area. The other thing we need to think about is, how can we extend the data? That will [probably consist of] looking at somatic mutations and other germline mutations.

References

1. Kindler HL, Hammel P, Reni M, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): phase III POLO trial. J Clin Oncol. 2019;37(18 suppl, abstr LBA4). doi: 10.1200/JCO.2019.37.18_suppl.LBA4.
2. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. doi: 10.1056/NEJMoa1903387.