Saif Shares Insights on Single-Agent PARP Inhibitors and Combination Therapies for Pancreatic Cancer

Studies evaluating PARP inhibitors, metabolic agents, and stroma-targeting strategies are contributing to advances in treatment for patients with pancreatic cancer, according to Wasif M. Saif, MD. As strategies veer toward precision medicine approaches, germline genetic testing will be critical, he said.

“Germline testing is extremely import- ant, not only [because] it tells us which patient has a genetic mutation linked to pancreatic cancer, but also because it advises us to look for other members in the family who may be at a higher risk of developing pancreatic cancer or other tumors, such as breast, ovarian, prostate, or colorectal cancer,” Saif said. “[Also], now we know based on the recent data from the POLO study [NCT02184195] that this testing will also help us decide [what] chemotherapy [should] be used for those patients.”

In an interview with OncLive^® in advance of the 39th Annual Chemotherapy Foundation Symposium^® (CFS^®), Saif, deputy physician in chief at Northwell Health Cancer Institute and a professor at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New Hyde Park, New York, discussed the evolving role of PARP inhibitors and anticipated trends for research in pancreatic cancer.

Why are PARP inhibitors necessary in the treatment of patients with advanced pancreatic cancer?

My presentation is related to the use of single-agent PARP inhibitors and combination therapies for pancreatic cancer. Pancreatic cancer accounts for approximately 3% of all cancers in the United States and approximately 7% of all cancer deaths. Despite the low prevalence [of the disease] relative to other solid tumors, we know that pancreatic cancer is one of the leading causes of cancer- related death in the United States. Pancreatic cancer is highly resistant to chemotherapy as well as radiation therapy. The current standard of care chemotherapeutic regimens, FOLFIRINOX [leucovorin, 5-fluorouracil, irinotecan, oxaliplatin] and gemcitabine plus nab- paclitaxel [Abraxane], provide disease control, but eventually [the] tumor develops chemotherapy resistance.

Tumors that are deficient in DNA damage repair mechanisms, such as [those with] BRCA mutations, respond better to platinum-based chemotherapy. However, these tumor cells can utilize the PARP [protein] as a salvage DNA repair pathway to pro- long survival. Hence, in the presence of a BRCA mutation, the inhibition of the PARP pathway can lead to tumor cell death. This provides a rationale for the use of PARP inhibitors in patients with BRCA-mutated pancreatic cancer.

Which agents have generated the most interest?

Of interest is olaparib [Lynparza], which [was approved by the] FDA based on the results of the phase 3 POLO study [NCT02184195]. The study results showed a doubling of progression-free survival with olaparib compared with placebo as maintenance therapy following frontline platinum-based chemotherapy in patients with advanced BRCA-mutant pancreatic cancer. Other PARP inhibitors include veliparib and rucaparib [Rubraca], which are being tested in pancreatic cancer both as single agents as well as in combination with systemic chemotherapy.

Other important DNA-affecting targets include ATM as well as CLB2 and CHEK2.

Why is it important to understand a patient’s genetic profile before initiating treatment?

It is now recommended by the National Comprehensive Cancer Network [NCCN] that we should be testing all patients who [receive a diagnosis of] pancreatic cancer for germline mutations. The NCCN has also suggested that patients who have somatic mutations can benefit from these targeted agents.

Germline mutations occur in the gametes and can be passed down to offspring, which means that every cell in the entire organism will be affected. On the other hand, somatic mutations occur in a single body cell and cannot be inherited; only tissues derived from that mutated cell are affected. It’s very important that patients should be tested for these genes.

Germline mutation testing must include BRCA1, BRCA2, [and providers should also consider testing for] microsatellite instability, ATM, and PALB2. It is extremely important that we don’t forget about test- ing the tumor. It’s not only [important] that we learn about the disease and the stage, but it’s also important that we know about the molecular or the genetic makeup of the tumor. That should be part of the initial work-up [and] will really guide treatment of the patient.

The phase 3 Avenger 500 trial (NCT03504423) investigated the antimitochondrial agent devimistat (CPI-613). How could this agent potentially be used?

Devimistat is a novel lipoate analog that inhibits the TCA [tricarboxylic acid] cycle. It inhibits the dehydrogenase enzyme and α-ketoglutarate dehydrogenase complexes. The benefit is that by [targeting these complexes], [the agent] inhibits the entry of glucose- and glutamine-derived carbon, respectively. Pancreatic cancer is dependent on mitochondrial function for enhanced survival and aggressiveness. A phase 1 study [NCT01835041] cited in Nature evaluated the combination [of] modified FOLFIRINOX and devimistat, [and] the results showed a very high response rate of 61% with a complete response rate of 17%. Now the randomized phase 3 Avenger 500 study is looking at devimistat in combination with modified FOLFIRINOX vs FOLFIRINOX alone for patients with untreated metastatic pancreatic cancer.

This study is important [because] we know the fibrotic microenvironment may [have] an advantage in causing resistance to chemotherapy, but we also know that it triggers a lot of metabolic hindrances and constraints on the tumor. A lot of studies have indicated that autophagy is essential in the tumor cell as well as in supporting the stroma, which is consistent with metabolic stress. We believe that devimistat will enrich the TCA cycle and may be particularly effective against tumors that have baseline metabolic stress, such as pancreatic cancer.

I hope that Avenger 500 will provide important data on the validity of this approach and further our understanding of the role of mitochondrial metabolism in therapy response in the first-line treatment of patients with metastatic pancreatic cancer [FIGURE].

What other areas are under investigation?

We are still trying to figure out sequential therapy. We’re trying to [better under- stand] what regimen [should] be used [in the] first-line [setting], [although a] BRCA1 [mutation can guide our choice]. We’re also learning about GATA6, which is a transcription factor, and is based on a special subclassification of pancreatic cancer, [that is] based on the Bailey, Collisson, or Moffitt classification.

We believe that certain subtypes of pancreatic cancer lack or are deficient in the GATA6 transcription factor, and we believe that those cell lines are resistant to FOLFIRINOX, which [currently] is the most aggressive [and] more successful regimen. There will be studies looking at those precision oncology approaches [and] sequential therapy. We are trying to [bring regimens used in] the metastatic [setting] to earlier stages of pancreatic cancer.

We are still learning about the pharmacogenetics and metabolic markers of chemotherapeutic agents, and we’ll be looking at pharmacokinetics and other pharmacodynamics. We’re still struggling with the stromal targeting agents. The HALO-301 study [NCT02715804] looked at combinations with chemotherapy, but we [still] need to learn [more about these agents].

Inflammatory response is very important, and JAK1 and JAK2 inhibitors have been tested in pancreatic cancer in a phase 1/2 study [NCT01858883]. Even though the study did not meet the end point, it did give us some answers, particularly [ragarding] cachexia, which is a huge challenge in pancreatic cancer. Multiple pathways are being investigated at this time, and I believe [that research] will continue.

There is rekindling interest in immunotherapy. Immunotherapy has not been very successful in pancreatic cancer, but we are learning more about it. From experience, [there is] a strong rationale to combine PARP inhibitors with immunotherapy. One of the theories is that PARP inhibitor-mediated DNA damage can really enhance the recruitment of T cells, which can lead to an upregulation of PD-L1 and [create] a good environment to be attacked with a checkpoint inhibitor. Clinical trials are looking at these things.

Now we are in the stage where neoadjuvant chemotherapy is being tested. The PREOPANC-3 [NCT04927780] and NEOLAP [NCT02125136] trials are 2 examples of that. We’re moving in a [good] direction here. We think a systemic disease should be treated systemically. Surgery is the only potential cure, we cannot deny that, but we really need to make sure to select the right patients for surgical resection.

[Investigators are looking at] the best way to give radiation therapy with less toxicity, such as [with] SBRT [stereotactic body radiation therapy]. We are also looking into liver-directed therapy in selected patients. Now we’re looking at pancreatic cancer from all angles, including the clinical and biological aspects of this disease, because we are able to see somewhat improved survival [by doing so] in a subset of patients, which gives us hope that we can do better than what we have done historically.

What else are you looking forward to sharing during the meeting?

[First is] the resistance to PARP inhibitors, and I’ll be talking about the ATR/ CHK1 pathway. We always say that there is a lifespan to everything. Similarly, when we give a drug to a patient, either an antibody or chemo- therapy, [we know the patient will] develop resistance.

We’ll be discussing the steps to overcome resistance, [such as through] combinations with immunotherapy. Overall, CFS^® is always an exciting [event]. When I talk to folks about it across our health system, everybody gets excited because everybody sees a value in CFS^® since it is more clinically oriented and informs our current and future practice.

If you could relay 1 thing to your colleagues in the community setting, what would it be?

The key take-home message is to know the patient, know the tumor, and know the cancer drug. You need to know the tumor stage and genetics because that’s how you are going to define the first-line therapy and think about maintenance therapy or a clinical trial. [You also have to] know the patient and what they are willing to accept. What are the patient's characteristics, comorbid conditions, and acceptance about chemotherapy adverse effects? That is really an important part [of the process]. Make sure the patient understands what you’re talking [about] and [that] you understand what [the] patient is asking for.