Genetic Testing, PARP Inhibitors Lead to Transformed Pancreatic Cancer Paradigm

Eileen M. O’Reilly, MD

Conducting germline testing on patients with pancreatic cancer, and potentially treating them with PARP inhibitors in the maintenance setting, has become a novel approach in the paradigm, according to Eileen O’Reilly, MD.

“The area that is of great interest is DNA damage repair (DDR) gene targeting and strategies in pancreatic cancer, both clinically and preclinically, and being able to understand the biology and signals that we can build upon,” said O’Reilly, associate director for clinical research at Memorial Sloan Kettering Cancer Center. “We want to build on first-line platinum-based [therapy] for this patient population, along with PARP inhibitors and maintenance approaches. Maintenance approaches in pancreatic cancer are starting to gain some use and some real data that we can add to going forward.”

For example, in December 2019, the FDA approved the PARP inhibitor olaparib (Lynparza) for the maintenance treatment of adult patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on ≥16 weeks of a frontline platinum-based chemotherapy regimen.

The approval was based on data from the phase III POLO trial, which showed a progression-free survival (PFS) benefit with olaparib versus placebo in this setting. The median PFS with the PARP inhibitor was 7.4 months compared with 3.8 months with placebo (HR, 0.53; 95% CI, 0.35-0.81; P = .0035). After 2 years, 22.1% of patients had no disease progression compared with 9.6% of those who received placebo.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Gastrointestinal Malignancies, O’Reilly reflected on the treatment advances that are expanding the pancreatic cancer paradigm.

OncLive: What is the current state of genetic testing in pancreatic cancer?

O’Reilly: How can we maximize outcomes in advanced pancreatic cancer? Genetic testing, in particular germline testing, [is important] for patients with this disease. There is now a recommendation for universal germline testing because [previously], we missed [treating patients with a therapy they qualified for].

If a person has a germline BRCA1/2 or PALB2 mutation, platinum-based therapy is ideal. Usually, we will not have that information at the time of diagnosis, but if they do have one of these mutations, being able to incorporate a PARP inhibitor as part of treatment [is important]. The other thing I would [stress] is that [we could] deliver more treatment to more patients, and maximize outcomes with frontline and second-line therapies.

How have you seen olaparib impact the treatment paradigm since its approval?

We recognize that this is for a niche, but very important population. One of the questions going forward is how to build on this in terms of combinations and to see whether the use of PARP inhibitors might apply to patients who do not have a BRCA1/2 mutation. However, for example, if patients have DDR gene mutations, there are some groups that could benefit [from olaparib].

We also know that people with somatic BRCA1/2 mutations can equally experience value from olaparib as a maintenance approach. One very important point to think about when considering using these drugs is to not wait until the disease is progressing. We know that patients who are progressing on platinum-based therapy appear to have a high surrogacy for resistance to PARP inhibitors.

The sweet spot is stabilizing the disease and [getting patients to respond] to frontline treatment. Then, [physicians] can think about utilizing a PARP inhibitor as a way of de-intensifying treatment, offering more flexibility, and potential as a way for disease control. The nice thing about PARP inhibitors is that when they work, they can work really well.

What ongoing trials are exploring more PARP inhibitors in pancreatic cancer?

We know that in the field of breast and ovarian cancer adding a checkpoint inhibitor to a PARP inhibitor [has become popularized]. That is a popular area in pancreatic cancer right now, and there are a few trials that are about to launch on this.

One trial at MSKCC will open for patients with either germline BRCA1/2 or PALB2 mutations, other DDR mutation genes, and patients who have an excellent response to platinum-based therapy but are not identified in a gene context. We think there is a good rationale for exploring PARP inhibitor and immunotherapy combinations in this disease. SWOG will also open a trial that will extend this theme in smaller studies next year.

Other combinations of interest are adding VEGF-targeted agents to PARP inhibitors. There has been rationale [for this approach] in the ovarian cancer field, so we are hoping this might have some traction, but we have yet to study that.

What role could veliparib have in the pancreatic cancer treatment landscape?

Veliparib is not FDA approved in any setting right now. In a trial [that was presented at the 2020 Gastrointestinal Cancers Symposium], we looked at the addition of veliparib to cisplatin and gemcitabine in patients with untreated stage III/IV pancreatic cancer with a germline BRCA1/2 or PALB2 mutation. While we did not see benefit with the addition of veliparib in combination chemotherapy, we did see a very encouraging survival signal.

The other point is that there was a subset of patients who were on the triplet arm and, after a certain time point, toxicity was limiting. Chemotherapy was then dropped and there was an option for patients to continue the PARP inhibitor—that subgroup did really well with veliparib.

I would not leave the impression that veliparib is inactive, because it is active, but when concurrent with chemotherapy, it is then limited by myelotoxicity.

By the end of 2020, what do you hope physicians will accomplish in pancreatic cancer?

We will have a few studies in the immunotherapy space [for pancreatic cancer]. A Canadian trial is looking at upfront gemcitabine plus nab-paclitaxel (Abraxane) plus 2 checkpoint inhibitors: PD-L1 and CTLA-4 inhibitors. We are keen to see what that study shows on chemotherapy plus immunotherapy and how that resonates in pancreatic cancer.

Similarly, there is a randomized, 3-arm, phase II study of gemcitabine nab-paclitaxel with or without nivolumab (Opdivo) and with or without a CD40-directed agent. The [receptor molecule] is being used as an agonist and to alter the tumor microenvironment and potentially influence T cells to activate. We may see a signal there, because we saw a promising signal in the phase I study.

Other areas of interest are metabolism targeting in pancreatic cancer. The phase III AVENGER 500 study is treating patients with CPI-613; that will probably accrue this year. We might not have data in 2020, but we look forward to seeing how that reads out.

Another big study that includes chemotherapy is looking at nanoliposomal irinotecan in the frontline setting is a version of FOLFIRINOX compared with gemcitabine/nab-paclitaxel. This will also be important in terms of driving a new standard of care. This study is now open and will recruit over the next 15 to 18 months.

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.