Targeting DNA Damage Repair Pathways in Pancreatic Adenocarcinoma

Introduction

There have been tremendous advances in the treatment of metastatic cancer patients with the widespread incorporation of immune checkpoint inhibitors into clinical practice [1-7]. Unfortunately, in pancreatic adenocarcinoma, checkpoint inhibitors only appear to be effective in patients with microsatellite instability-high tumors, which comprises only 1% of patients with metastatic disease [8••, 9]. Five-year survival rates remain dismal in patients with metastatic disease at < 10% while the incidence of pancreatic cancer continues to increase [10]. Despite this, the treatment landscape for metastatic pancreatic adenocarcinoma (mPDA) is being redefined through novel targets which have emerged with the widespread incorporation of next-generation sequencing (NGS) tumor testing. Among the most promising of these targets are genes encoding for instrumental proteins which orchestrate DNA damage repair (DDR) and are responsible for ensuring genomic integrity in tumor cells in the face of replication stress and cytotoxic insults [11••]. Double-strand break repair is the most critical DDR pathway given unregulated double-strand breaks result in mitotic catastrophe [12]. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two double-strand break repair pathways, with HR most commonly utilized by eukaryotic cells because of its error-free nature [13]. Based upon the crucial role HR plays in maintaining cellular integrity, it is unsurprising why defects in HR machinery render tumor cells sensitive to DNA damage-inducing agents. Beyond novel targets, NGS has led to insights about optimal therapeutic sequencing for patients through identification of specific tumor signatures (e.g., choosing platinum chemotherapy in the first-line setting for patients with DDR-deficient tumors) [11••]. Inthesub-sequent paragraphs, we will discuss DDR targets and the therapeutics which have demonstrated promise in targeting them.

DDR

• The prevalence of somatic and germline mutations in DDR genes in mPDA is higher than previously reported with 17–25% of patients having tumors with these mutations [12, 13]. HR defects comprise most of these mutations in pancreatic tumors from aggregate data presented by Pishvaian et al. [11••].

• Patients with mPDA who have DDR mutations demonstrate markedly improved survival when exposed to platinum chemotherapy when compared to patients with DDR intact tumors (2.37 years versus 1.45 years, p < .0001). In the absence of exposure to platinum chemotherapy, patients with DDR-deficient tumors demonstrate no difference in survival compared to patients with DDR intact tumors.

• Although it was previously believed that only patients with germline DDR mutations benefit from DNA damaging agents such as platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors, several studies suggest this benefit also extends to patients with somatic mutations [14, 15••, 16••].

• Among DDR inhibitors, PARP inhibitors have the most clinical data in mPDA. There are, however, other DDR inhibitors targeting ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent polymerase kinase (DNA-PK), and WEE1 which have demonstrated preclinical and early clinical promise [17-19]. Tables 1 and 2 are a list of completed and ongoing PARP inhibitor studies in mPDA patients, respectively. Figure 1 illustrates the concept of synthetic lethality in HR-deficient cancer cell lines when both PARP and ATR are targeted.

Table 1.

Completed trials of PARP inhibitors in PDA patients

Trial number	Stage of study	PARP inhibitor (monotherapy or combination)	Number of PDA patients	Selection criteria (germline or somatic DDR mutations)	Primary outcome and key secondary outcome findings
NCT02184195	III	Olaparib	154	Germline BRCA	PFS 7.4 months PARP maintenance arm versus 3.8 months in placebo arm (HR .53, P = .004).
NCT01078662	II	Olaparib	23	Germline BRCA	RR 21.7%. No significant difference in RR between BRCA1 or BRCA2 mutants.
NCT02042378	II	Rucaparib	19	Somatic or Germline BRCA	RR 15.8%, with all responses observed in patients with platinum-sensitive disease.
NCT02184195	II	Veliparib	16	Germline BRCA and PALB2	RR 0%, with SD in 5 patients, all with platinum-sensitive disease. The tria was stopped early.
NCT01585805	II	Cisplatin and gemcitabine ± veliparib	50	Germline BRCA and PALB2	RR 74% in the triplet arm and 62.5% in the doublet arm. No significant difference in PFS and OS between the triplet and doublet arms
NCT01585805	I	Cisplatin, gemcitabine, and veliparib	17	Germline BRCA and BRCA WT patients	MTD at DL2. RR 77.8% in germline BRCA cohort and 0% in BRCA WT cohort.
NCT01296763	I	Olaparib, irinotecan, cisplatin, and mitomycin	18	Unselected	Addition of mitomycin was too toxic (3 DLTs) with 89% of the cohort experiencing G3/G4 AEs. The RR of all patients was 23%.
NCT01489865	I	FOLFOX plus veliparib	22	Germline BRCA, PALB2 or FANC mutation	RP2D of veLiparib 300 mg BID in addition to standard mFOLFOX 6 doses. RR of 14%, PFS 2.6 months and OS 5.4 months.

Abbreviations: Pancreatic adenocarcinoma—PDA; poly (ADP-ribose) polymerase—PARP; DNA damage repair—DDR; progression-free survival—PFS; hazard ration—HR; response rate—RR; recommended phase 2 dose—RP2D; maximum tolerated dose—MTD; dose level 2—DL2; overall survival—OS; grade—G; dose-limiting toxicity—DLT; adverse events—AEs

Table 2.

Ongoing trials with DDR-targeting agents in PDA patients

Trial number	Stage of study	DDR agent (monotherapy or combination)	Accrual target (patient number)	Selection criteria (germline or somatic DDR mutations)	Primary outcome
NCT03140670	II	Maintenance rucaparib	42	Germline or somatic BRCA and PALB2 mPDA patients who do not progress on platinum chemotherapy	6-month PFS
NCT02890355	II	FOLFIRI ± veliparib	143	2nd-line mPDA patients, unselected by DDR status	OS
NCT03553004	II	Niraparib	18	2nd-line mPDA patients with germline or somatic DDR (unspecified) mutations	RR
NCT03337087	I/II	Flurouracil, nanoliposomal irinotecan, and rucaparib	110 (not all mPDA patient)		Later-line mPDA patients for phase I, untreated mPDA with HR mutations (somatic or germline)
RP2D of phase I, RR in PDA patients with HR mutations in phase II
NCT02677038 NCT02511223	II	Olaparib	34	2nd-line and beyond germline BRCA-negative PDA patients with DDR mutations or family history of BRCA-associated malignancies	RR

Abbreviations: DNA damage repair—DDR; pancreatic adenocarcinoma—PDA; response rate—RR; recommended phase II dose—RP2D; homologous recombination—HR; overall survival—OS

Fig. 1.

Simplified figure illustrating how synthetic lethality is created in cancer cells, with background HR deficits (deleterious mutations in ATM pathway or BRCA), when treated with PARP inhibitors or ATR inhibitors. Crosses imply cells with intrinsic defects in the denoted proteins while –I denotes the target of the specific inhibitors. Abbreviations: MMB, mismatched base; PARP, poly (ADP-ribose) polymerase; DSB, double-stranded breaks; HR, homologous recombination; ATM, ataxia-telangiectasia mutated; ATR, ataxia-telangiectasia and Rad3 related.

PARP inhibitors—monotherapy

• PARP1 and PARP2 are enzymes involved in base excision repair which are normally recruited to sites of single-strand DNA breaks [20]. PARP inhibitors inhibit the enzymatic activity of both enzymes; however, their differential potency appears to be defined by PARP1 trapping, which represents an additional mechanism of action [21].

• Kaufman et al. presented findings from a phase II multi-cohort study of metastatic germline BRCA mutant patients treated with olaparib 400 mg twice daily [20]. Of the 298 patients who received at least one dose of olaparib, 23 patients had mPDA. Seventeen (74%) of these patients had BRCA2 mutations while one patient had both BRCA1/BRCA2 mutations; the median number of prior therapies was 2. Response rate (RR) in the pancreatic cancer patients was 21.7% compared to 26.2% in the entire cohort. Stable disease (SD) lasting ≥ 8 weeks was seen in 34.8% of mPDA patients compared to 41.8% of the entire cohort. RR between BRCA1 and BRCA2 mPDA were similar at 20% and 23.5%, respectively. There was no significant difference in RR between mPDA patients who did (20%) and did not (25%) have prior exposure to platinum-based chemotherapy. Median progression-free survival (PFS) and overall survival (OS) were 4.6 months and 9.8 months, respectively, in mPDA patients. Anemia (17.4%), fatigue (13%), abdominal pain (4.3%), and vomiting (4.3%) were the most common Grade (G) 3 or greater adverse events reported in the pancreas cohort.

• Shroff et al. presented results from the global RUCAPANC (NCT02042378) phase II study exploring the role for rucaparib in mPDA patients with germline or somatic BRCA1/BRCA2 mutations [14]. In this study, 19 patients, with a median of two prior lines of systemic therapy, were treated with rucaparib 600 mg twice daily. Of these patients, 16 (84.2%) had germline BRCA mutations while 3 (15.8%) had somatic mutations. Fifteen (78.9%) patients had tumors with BRCA2 mutations while four (21.1%) had tumors with BRCA1 mutations. RR was 15.8% across the entire cohort with two patients achieving a confirmed partial response (PR) and one achieving a complete response (CR). There was an additional patient who achieved SD for 72 weeks and, just prior to study discontinuation, was classified as having an unconfirmed CR. None of the patients with confirmed or unconfirmed responses had progressed on prior platinum chemotherapy. The disease control rate (DCR) was 31.6% in all patients and 44.4% in patients who had received only one prior chemotherapy regimen. The most common G3/G4 adverse events were anemia (31.6%), fatigue (15.8%), ascites (15.8%), thrombocytopenia (10.5%), vomiting (10.5%), increased transaminases (10.5%), abdominal pain (10.5%), and nausea (10.5%).

• Lowery et al. presented findings from a phase II study which explored the efficacy of veliparib in pre-treated germline BRCA and PALB2 mutant (44% with 1 prior line, 56% with 2 prior lines of systemic therapy) PDA patients; 94% of patients were metastatic while 6% were locally advanced [22]. A total of 16 patients (31% BRCA1, 69% BRCA2) were enrolled and treated with veliparib 400 mg twice daily (the first 3 patients were treated at 300 mg twice daily to ensure tolerance). The RR was 0%, and DCR was 31%, with stable disease in five patients. The trial was stopped early for futility based upon its pre-specified efficacy threshold. One patient who remained progression-free for 9.5 months while on therapy had previously been platinum chemotherapy sensitive and had a PR to FOLFIRINOX for 6 months. All five of the patients with SD had prior platinum chemotherapy responsiveness. G3/G4 adverse events were observed in 69% of patients with the most common ones being fatigue (25%) and hyperbilirubinemia (19%).

• Gollian et al. reported on the efficacy of olaparib in mPDA patients without BRCA mutations but with other DDR-deficient phenotypes which the authors termed “BRCAness [15••].” This is an ongoing two-arm parallel phase II study conducted in the USA and Israel, and 32 patients with at least prior line of systemic therapy have been treated at olaparib 400 mg twice daily. The phenotypes of patients who have been treated on study include 12 with tumors with DDR mutations (6 with ATM, 2 with somatic BRCA2, and 1 each with PALB2, FANC2, PTEN, and CCNE mutations), 5 with tumors with ATM loss by immunohistochemistry, and 14 with a family history of BRCA-associated malignancy without germline alterations. RR in the US cohort is 18.1% while in the Israeli cohort is 0%. DCR in the US cohort is 72.7% while in the Israeli cohort is 29.4%. Median PFS is 14 weeks and 24.7 weeks in the Israeli and US cohorts, respectively. No G3/G4 toxicities were reported in the study at the time of presentation.

• Based on prior findings that rucaparib only demonstrated response in mPDA patients who were platinum chemotherapy sensitive, Reiss et al. conducted a phase II study of maintenance rucaparib in 42 patients with tumors with pathogenic mutations in BRCA1/BRCA2 or PALB2 (germline or somatic) who had not progressed on platinum chemotherapy [16••]. Participants in the study had received at least 4 months of prior platinum chemotherapy and achieved disease control prior to starting 600 mg twice daily of rucaparib. At the time of the interim analysis, 19 of 24 patients were evaluable for response. RR was 37% with 1 CR and 6 PR while DCR for at least 2 months was 90%. The median PFS in treated patients was 9.1 months. G3/G4 adverse events were not specifically reported but common adverse events included nausea, dysgeusia, and fatigue.

• Golan et al. presented findings from the POLO trial (NCT02184195), a randomized phase III study in which 154 patients with germline BRCA1/BRCA2 mutant mPDA who had not progressed after at least 16 weeks first-line platinum chemotherapy were randomized in a 3:2 fashion to olaparib 300 mg twice daily or placebo [23••]. The primary endpoint of the study was PFS while secondary endpoints included OS and RR. Median PFS in the experimental arm was 7.4 months while that in the in the placebo arm was 3.8 months (hazard ratio (HR) .53; 95% confidence interval (CI), .35–.82; P = .004). At the time of interim analysis, after data maturity in 46% of the study population, median OS in the olaparib and placebo arms was 18.9 and 18.1 months, respectively (HR .91; 95% CI, 0.56 to 1.46; P = 0.68). Among patients with measurable disease at baseline, RR was 23% in the study arm and 12% in the placebo arm; median duration of response was 24.9 months in the study arm and 3.7 months in the placebo arm. Serious adverse events were experienced by 24% and 15% of patients in treatment and placebo arms, respectively; 10% of patients treated with olaparib experienced ≥ G3 anemia. Based on these study findings, olaparib received FDA approval as a maintenance therapy for germline BRCA mutant PDA patients with non-progressive disease after initial platinum chemotherapy.

• From the previously described studies, PARP inhibitors appear to have the most anti-tumor activity in mPDA patients who remain sensitive to platinum chemotherapy. Platinum-sensitive clinical phenotype may be a surrogate for a HR-deficient genotype. PARP inhibitors have mostly been tested in patients who have germline DDR mutations (BRCA and beyond) however appear to also have anti-tumor effects in patients with somatic DDR mutations. PARP inhibitor monotherapy in mPDA, whether in maintenance or later-line settings, appears to have less activity than PARP inhibitors in other disease sites where they are routinely utilized [24•, 25].

PARP inhibitors—combined therapy

• Beyond PARP inhibitor monotherapy, combinations of the agents with chemotherapy have also been trialed. Yarchoan et al. enrolled 18 mPDA patients on a two-center phase I study and treated them first with the combination of olaparib (twice daily day(D)1, D8), cisplatin (D1, D8), and irinotecan (D1, D8) [26]. The maximum tolerated dose (MTD) of this combination was cisplatin 25 mg/m² D1, D8; irinotecan 70 mg/m² D1, D8; and olaparib 100 mg twice daily on D1, D8. After this MTD was achieved, the investigators explored the safety and tolerability of adding mitomycin 5 mg/m² on D1. Only six patients received the mitomycin addition and tolerated it poorly with two patients developing G4 neutropenia and one patient developing G3 febrile neutropenia. Given the three observed dose-limiting toxicities (DLTs), the combination was deemed too toxic. Thirteen patients had received two or more lines of therapy while three patients had received one prior therapy line; two patients were known BRCA2 mutants. Safety data was collected for the entire cohort, and 16 (89%) patients developed G3/G4 toxicities with the most common toxicities being neutropenia (89%), lymphopenia (72%), and anemia (22%). Thirteen patients were evaluable for response while five came off therapy prior to the first evaluation. RR was 23% with three PR, and DCR was 62%. Among the two patients with BRCA2 mutations, one achieved a PR for 4 years prior to succumbing to therapy-associated acute myeloid leukemia while the other achieved SD for 3 months.

• O’Reilly et al. presented findings from a phase I trial of cisplatin, gemcitabine, and veliparib in 17 advanced PDA patients (88.2% metastatic, 11.8% locally advanced) [27]. Two cohorts of patients (nine with germline mutated BRCA, seven with wildtype BRCA, and one with unknown BRCA status) were enrolled in the study and treated with gemcitabine 600 mg/m² D3, D10; cisplatin 25 mg/m² D3, D10; and veliparib at escalating doses on every 21-day cycle. MTD was reached at dose level 2 of veliparib at a dose of 80 mg twice daily on D1-D12. The dose level 2A (D1–21) dosing of veliparib was too toxic for patients with 4 DLTs (50% neutropenia, 50% thrombocytopenia) observed. There were two G5 events in the entire patient cohort with one patient developing therapy-associated AML and the other suffering from a colonic perforation. RR was 77.8% in BRCA mutant patients with one CR and six PR while DCR was 100%. In the BRCA wildtype patient cohort, RR was 0% and DCR was 85.7%. Median OS was 23.3 months and 11 months in BRCA mutant and wildtype patients, respectively.

• Findings from the phase I study of cisplatin, gemcitabine, and veliparib established the dose for the combination used in the randomized phase II portion of the study comparing the efficacy of cisplatin and gemcitabine ± veliparib in 50 germline BRCA- and PALB2-mutated patients. O’Reilly et al. recently presented the findings from this portion of the trial [28••]. Patients were randomized to either gemcitabine 600 mg/m² D3, D10; cisplatin 25 mg/m² D3, D10; and veliparib 80 mg D1-D12 every 21 days or gemcitabine and cisplatin at the same schedule. The primary endpoint of the study was RR in each arm with secondary endpoints of PFS, DCR, and OS. The RR was 74% in the triplet arm and 65.2% in the doublet arm, with both arms exceeding pre-specified response thresholds to move to the subsequent stage of the trial. Median PFS was 10.1 months for the triplet arm and 9.7 months for the doublet arm (P = .73). Median OS was 15.5 months for the triplet arm and 16.4 months for the doublet arm (P = .6). Patients treated with the triplet combination experienced more than twice the number of hematologic G3/G4 toxicities (53%) compared to patients treated with the doublet combination (22%). The 2-year survival for the entire cohort was 30.6% (95% CI, 17.8–44.4%). The study results suggest that while veliparib may not have added additional PFS or OS benefit to gemcitabine plus cisplatin in BRCA- and PALB2-mutated advanced PDA patients, gemcitabine plus cisplatin is a highly active combination in PDA tumors with such germline mutations.

• Pishvaian et al. reported the final findings from the phase I/II study of modified FOLFOX 6 (D1–D3) plus veliparib (twice daily on D1–D7) every 14 days in advanced PDA patients at ASCO 2019 [29]. The recommended phase 2 dose (RP2D) of the combination was veliparib 200 mg twice daily along with standard doses of modified FOLFOX. No DLTs were observed in the phase I portion of the study. In the phase II portion of the study, two cohorts of patients were enrolled (treatment naive and pre-treated) and were pre-selected if their tumors carried germline or somatic mutations in BRCA1/2, PALB2, and ATM and if they had family histories suggestive of a breast or ovarian cancer syndrome. Of 57 patients evaluable for response, RR was 26%, median PFS was 3.7 months, and median OS was 8.5 months. In patients with a family history suggestive of breast and ovarian cancer syndrome (N = 43), median PFS and OS were 4.3 and 10.1 months, respectively. In patients with tumors with DDR mutations (N = 16), median PFS and OS were 7.2 and 11.1 months, respectively. Intriguingly, in treatment naive patients with positive family history and DDR mutant tumors, ORR of the combination was 58%.

• PARP inhibitors in combination with platinum chemotherapy elicit a higher RR in advanced PDA patients than chemotherapy alone however whether that translates to a PFS or OS benefit is unclear. Patients with tumors with DDR mutations, either germline or somatic, appear to derive a disproportionate benefit from the treatment combinations compared to patients with tumors with intact DDR. PDA patients with germline mutations in BRCA or other HR genes may be especially sensitive to platinum chemotherapy, even as a monotherapy.

Therapies beyond PARP inhibitors

• ATM is one of the two most upstream kinases which coordinates the DDR response and is stimulated by double-strand breaks. It activates downstream effectors such as Chk2 and TP53 which play crucial roles in directly orchestrating DNA repair and cell cycle arrest [30•]. Perkhofer et al. reported findings from cell line models of ATM-deficient PDA (AKC) suggesting these cell lines were particularly sensitive to ATR inhibition [17]. The AKC cell lines were more sensitive to ATR inhibition than the KC (ATM intact PDA) cell lines by IC50. The authors then investigated the effect of the ATR inhibitor VE-822 in a subcutaneous transplantation model. VE-822 significantly reduced tumor progression in the AKC model while it had minimal effects in the KC model. Adding gemcitabine to VE-822 increased the tumor stabilizing effect in AKC models while not meaningfully slowing tumor growth in KC models.

• The ATM inhibitor AZD0156 has been trialed preclinically in combination with cisplatin in patient-derived pancreatic cancer cell lines [31]. Even in cell lines devoid of DDR deficiencies, AZD0156 sensitized the tumor cells to cisplatin, suggesting the ability of the inhibitor to create a DDR-deficient tumor phenotype.

• ATR is a primary DDR kinase which is stimulated by single-strand intermediates and replication stress [30•]. Wallez et al. reported findings from experiments with the ATR inhibitor AZD6738 in combination with gemcitabine in mouse PDA cell lines, human PDA cell lines, and a TP53- deficient subcutaneous PDA model [18]. All four cell lines from the KPC mouse model (KRAS G12D, TP53 R172H) were very sensitive to AZD6738 monotherapy alone. Several human PDA cell lines which demonstrated intrinsic resistance to the ATR inhibitor included MiaPaCa-2 and Panc-1. Upon further interrogation, the investigators found these cell lines upregulated ATM and DNA-PK when exposed to AZD6738. In clonogenic survival assays of both cell lines, this resistance was able to be overcome with the addition of gemcitabine. AZD6738 plus gemcitabine was tested in vivo in K8484 allograft models. For this part of the experiment, allograft mice were treated in each of the four arms, AZD6738 monotherapy at 25 mg/kg 5 days per week, gemcitabine monotherapy 100 mg/kg twice per week, placebo, and the combination. In the AZD6738 monotherapy arm, there was no tumor shrinkage or slowing of growth while in the gemcitabine monotherapy arm there was slowing of growth without shrinkage. In the combination arm, 7 of 10 mice demonstrated tumor shrinkage by the end of week 3 of treatment. There was no significant change in mouse body weight in the combination arm compared to the monotherapy arms.

• Estrada-Bernal et al. explored the radiosensitizing ability of the MEK1/2 inhibitor trametinib (GSK212) in KRAS mutant PDA cell lines MIAPaCa-2 and AsPC-1 [19]. In clonogenic survival assay experiments, the authors found pre-treating MIAPaCa-2 for 24 h or 48 h with 10 nm of trametinib sensitized the cells the ionizing radiation. This was not observed when the cells were pre-treated just prior to radiation with the MEK inhibitor or if the drug was administered 1-h post-radiation, suggesting that sustained MEK1/2 pathway inhibition is what creates radiosensitivity in these cell lines. Because non-homologous end joining (NHEJ) and HR are the DDR mechanisms triggered by radiation, the investigators wanted to assess the specific mechanism by which trametinib radiosensitized the PDA cell lines. The authors demonstrated this by pre-treating MiaPACa-2 cells with trametinib 24 h prior to administered ionizing radiation. The MEK inhibitor blunted NHEJ through decreasing expression of DNA-PK and blunted HR through downregulating BRCA1 and RAD51 expression.

• TP53 is mutated in > 70% of PDA, leading to loss of the G1/S checkpoint and dependence on the G2/M to maintain genomic integrity [31, 32]. WEE1 is a key regulator of the G2/M checkpoint through its inactivation of CDK1, and thus, WEE1 inhibitors may play a therapeutic role in this disease [33].

• A phase I study in 34 locally advanced PDA patients tested the WEE1 inhibitor AZD1775 (adavosertib) in combination with gemcitabine and radiation therapy [34]. Patients in the study received 4 cycles of oral adavosertib D1, D2 and D8, D9 (100–175 mg), IV gemcitabine 1000 mg/m² D1, D8, and radiation during cycles 2 and 3. Each cycle was 21 days. The RP2D of adavosertib was chosen to be 150 mg in the setting of the DLTs (anorexia, nausea, and fatigue) experienced by 33% of study patients. Median OS in the study patients was 21.4 months while median PFS was 9.4 months.

Summary

DDR mutations may represent an Achilles’ heel of advanced PDA and are present in 17–25% of tumors. Beyond patients with germline BRCA- and PALB2-associated tumors, patients with tumors that harbor somatic DDR mutations appear to also derive differential benefit from agents such as PARP inhibitors and platinum chemotherapy. Patients who appear to derive the greatest benefit from PARP inhibitors, from existing clinical trials, appear to be those who possess platinum-sensitive tumors and are given the agents in combination with DNA damaging cytotoxic therapy. The role for maintenance therapy with PARP inhibitors after platinum chemotherapy has been established in patients with germline BRCA mutations however needs more definitive exploration in patients with somatic DDR mutations. Furthermore, whether PARP inhibitors should be administered with other agents in the maintenance setting to maximize efficacy needs prospective evaluation. Beyond PARP inhibitors, an array of DDR-targeting agents have demonstrated preclinical promise in DDR-deficient PDA models and include ATM, ATR, DNA-PK, and WEE1 inhibitors; clinical validation remains pending. We still have much work to do in order to improve outcomes for patients with PDA; however, the future appears promising given our improved mechanistic understanding about the biology of the disease and development of potent therapeutics which seek to exploit some of these mechanisms.

Opinion statement.

Metastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment Lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.