Pancreatic ductal adenocarcinoma (PDAC) cancer is an aggressive malignancy. In United States, it is currently the third leading cause of cancer-related mortality [1
]. Most patients have advanced (locally advanced unresectable or metastatic) disease on presentation [2
] and despite advances in development of multiagent cytotoxic regimens [3
], the overall five-year overall survival (OS) is less than 10% [1
]. There is an unmet need to develop new treatment strategies. Personalized, biomarker-based options for patients with advanced PDAC do exist, i.e., pembrolizumab for microsatellite instability-high (MSI-H)/mismatch repair deficient (d-MMR) [8
] and larotrectinib for tumors with neurotrophic receptor tyrosine kinase (NTKR) gene fusions [9
], but this accounts for <1% of total patient population.
Approximately 5–10% PDAC cases are hereditary in nature and are associated with germline mutations in BRCA 1
, ATM, CDKN2A, STK11
(Peutz-Jeghers syndrome) and MLH1, MSH2, MSH6, PMS2
, and EPCAM
(Lynch syndrome) [10
]. Approximately 4–7% of patients with PDAC have germline BRCA1
]. Beyond screening and potentially early detection, identification of these mutations has potential therapeutic implications as they confer increased sensitivity to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi) [16
]. Specifically, PARPi lead to unrepaired accumulation of single strand DNA breaks (SSBs) that eventually culminate into double strand breaks (DSBs), which, in the presence of BRCA1/2
mutations and resulting deficiency in the homologous recombination (HR) repair mechanism, remain unrepaired, leading to cell death [17
In this review, we would discuss the mechanism of action of PARPi, clinical applications in advanced PDAC, resistance mechanisms as well as opportunities for future development of these agents in PDAC.
4. Resistance Mechanisms
The various mechanisms through which tumor cells acquire resistance to PARPi have been illustrated in Figure 3
. Several studies suggested that acquired BRCA
mutations in patients with gBRCA1/2
could lead to restoration of HR and confer resistance of platinum agents and PARPi. An in vitro study by Sakai et al. [106
] demonstrated that intragenic mutations in BRCA2
mutant PDAC and ovarian carcinoma cell lines restore the BRCA2
reading frame leading to both cisplatin and PARPi. Norquist et al. [107
] showed that these secondary reversion mutations were found in 29% of gBRCA1/2
mutant recurrent ovarian carcinomas and were predictive of resistance to platinum containing chemotherapy and PARPi. A UK study [108
] demonstrated olaparib resistance with emergence of a secondary BRCA2
mutation with restoration of its function.
In the absence of BRCA2
reversion mutations, tumor cells can evade lethality by PARPi through protection of RF. Chaudhuri et al. [36
] showed that deficiencies of MLL3/4 in BRCA2
mutant cells inhibits the recruitment of MRE11 to the RF in vitro, thereby preventing the RF degradation. Furthermore, 53BP1 regulates the balance between HRR and NHEJ [111
]. 53BP1 loss downregulates NHEJ and promotes error free HR, thereby conferring resistance of PARPi [111
]. Finally, microRNAs can modulate sensitivity to PARPi. For example, miR-107 and miR-222 downregulate expression of RAD51, thereby impairing DDR by HR and enhancing sensitivity to olaparib [112
]. In addition, miR-622 mediated resistance to PARPi and cisplatin in BRCA1
mutant cells by diverting the repair towards HR pathway and suppressing the NHEJ via Ku complexes [113
DDR is dependent on the phase of cell cycle; modulating cell cycle checkpoints can potentially alter the effect of PARPi in tumor cells. Inhibition of CDK12 leads to downregulation of DDR genes [114
] and reverses resistance to PARPi in breast cancer [115
] and multiple myeloma in vitro [116
]. PARPi-induced DNA damage can activate the ATR-mediated G2/M checkpoint facilitating DNA repair which can be reversed by ATR inhibition leading to cell death [117
]. Similarly, Wee1 inhibition can allow unrepaired DNA enter mitosis via the G2/M checkpoint but the results of phase I study with olaparib with Wee1 inhibitor in unselected were disappointing with ORR of only 11% [118
]. MET phosphorylates PARP1 at Tyr907, increases its enzymatic activity thereby reducing the affinity for PARPi and leads to resistance [119
]. PARPi in combination with a MET inhibitor can overcome PARPi resistance in vitro [120
]. The phosphoinositide 3-kinase (PI3K) signaling pathway has a role in tumorigenesis through maintenance of HR steady state [121
]. A study in TNBC showed that PI3K inhibition leads to sensitization to PARPi by downregulation of BRCA1/2
, increased poly ADP-ribosylation and DNA damage [122
]. Finally, in BRCA-deficient cells, resistance due to upregulation of genes responsible for p-glycoprotein with subsequent increased efflux of PARPi can develop, which can be counteracted by p-glycoprotein inhibitors [123
]. A next generation PARPi (AZD2461), that is not a substrate for p-glycoprotein is in development and is thought to potentially overcome p-glycoprotein-mediated olaparib resistance [124
Advanced PDAC is one of the most challenging malignancies to treat. PDAC is catching up with the current wave of precision medicine with the goal of improving patient outcomes. Besides two tissue-agnostic therapies (pembrolizumab for MSI-H/d-MMR and larotrectinib for NTRK fusion gene positive tumors), PARPi are an exciting addition to our armamentarium of drugs for patients with pathogenic gBRCA1/2
mutations and olaparib is endorsed by the National Comprehensive Cancer Network (NCCN) as appropriate maintenance therapy after at least 4 months of platinum-based therapy provided that there is no interim disease progression [125
]. With the advent of emerging clinical data, there are several questions that remain answered.
Firstly, whether the benefit seen in the gBRCA
mutant patients in POLO trial could be extrapolated to tumors with somatic BRCA
mutation or in patients with other HRD or DDR mutations remains unclear. The one patient with somatic BRCA2
and the two patients with gPALB2
mutations enrolled in the maintenance rucaparib study so far (24 out of 42 planned patient accrual) attained an objective response indicating that the benefit of PARPi potentially extends beyond gBRCA1/2
]. Data from a large number of clinical trials (NCT02042378, NCT02677038, NCT02511223, NCT03140670, NCT02890355, NCT01489865) evaluating the role of PARPi in patients with somatic mutations would provide further clarity regarding the extent and durability of response in this group of patients. The NCCN endorses testing patients for infrequent but potentially actionable somatic alterations including BRCA1/2
]. Whether archival or fresh tissue should be used for somatic mutation screening is unclear. Data from retrospective ovarian cancer tumor sample analysis suggests that BRCA1/2 loss occurs early in the course of the disease [126
] but it is not currently known if this is true in PDAC. Validation of predictive biomarkers beyond gBRCA1/2
mutations, NTKR fusions, and MMR/MSI status is an unmet need in PDAC.
Secondly, the appropriate timing of the use of PARPi in the disease course of PDAC is unclear. As mentioned in the sections earlier, PARPi are being tested both as monotherapy (maintenance and refractory) and in combination with other agents (front-line and subsequent lines of treatment).
In the maintenance setting, olaparib led to PFS benefit in gBRCA1/2
platinum sensitive patients in POLO trial [66
]. However, it is important to note that the preliminary data suggest no OS benefit and it is possible that use of PARPi in subsequent lines of therapy can be as beneficial as in the maintenance setting, but whether this is dependent on platinum sensitivity is unclear. Rucaparib in patients with somatic or germline BRCA1/2
] and olaparib in patients with BRCAness
] showed benefit only in platinum-sensitive disease, while with olaparib in patients with gBRCA1/2
, the benefit was seen irrespective of the platinum-exposure [56
]. Unfortunately, the initial report of the POLO study does not mention subsequent use of PARPi in patients treated with placebo. In addition, whether PARPi is superior to 5-FU maintenance as used in the PANOPTIMOX study is unknown [127
]. There is currently no head-to-head comparison between maintenance PARPi and chemotherapy. Also, the appropriate time to switch therapy to PARPi is unclear. In the POLO trial [66
], one-third of patients received platinum-based therapy for more than 6 months. On subgroup analysis for PFS, patients who received platinum-based therapy for >6 months seemed to have a greater benefit (HR 0.35, 95% CI 0.17–0.72) as compared to 4–6 months (HR 0.69, 95% CI 0.43–1.12). Finally, it is unclear if there is any benefit to platinum re-induction after progression on PARPi. Preclinical data reveal cross-resistance between PARPi and platinum chemotherapy [128
] and, in an unselected patient population in the PANOPTIMOX study, reintroduction of FOLFIRINOX (folinic acid + 5-FU + irinotecan + oxaliplatin) upon disease progression led to a marginal benefit of 1.4 months in terms of median PFS [PFS1 (defined as time to first progression of disease) of 5.7 mo, PFS2 (defined as time to disease progression during FOLFIRINOX) of 7.1 mo [127
]. Using an alternative alkylating agent such as mitomycin C, might be preferable to platinum re-induction but only anecdotal evidence exist so far [129
]. Furthermore, there is no data to support switching from one PARPi to another at the time of disease progression.
Is it time to start using PARPi in combination with chemotherapeutic agents, be it in the first or subsequent lines of treatment? Though the mFOLFOX-6 plus veliparib combination was promising, especially in highly selected patients who are platinum-naïve and have DDR mutation and BOCS history, the lack of direct comparison to chemotherapy limits the upfront use of this strategy [75
]. As a cautionary tale, SWOG S1513 showed detrimental effects for the combination, even for the subgroup of patients with DDR mutations [74
]. Both trials showed an increased toxicity profile with the combination arms, indicating that the benefit of the combination (if at all) would potentially come at the cost of an increased toxicity [74
]. The direct comparison of gemcitabine/cisplatin with and without veliparib in front-line setting in BRCA1/2/PALB2
mutated PDAC will provide further insight [80
]. Several other clinical trials are evaluating PARPi in combination with different chemotherapies in front-line (NCT01282333) or subsequent lines of therapy (NCT03337087, NCT01233505, NCT00515866).
Though relatively well tolerated, PARPi do have a toxicity profile that needs to be kept in mind while making therapy decisions and it is important to understand that different PARPi differ in their potencies for catalytic inhibition, PARP binding, and inhibition of PARylation; and hence, have differing toxicity profiles and potentially efficacy and therefore, cannot be assumed that can be used interchangeably. For example, rucaparib leads to elevated creatinine based on inhibition of renal transport proteins and has the highest rate of transaminitis [63
]. On the other hand, niraparib has the highest rate of bone marrow suppression and resultant hematologic toxicities [64
]. In POLO study [66
], the PFS benefit came at the cost of increased incidence of grade 3 AEs. Even though there was no notable deterioration in QoL, it is worth noting that majority (67%) of the patients had excellent performance status (ECOG 0). In the real world, the PFS benefit could come at the cost of increased toxicity profile and QoL deterioration, as majority of PDAC patients do not have preserved performance status.
Beyond early identification of patients with gBRCA1/2 pathogenic mutations, how can we better select patients for PARPi maintenance after platinum therapy? The development of reversion somatic BRCA2 mutations during platinum-based therapy that limits the efficacy of PARPi. Tumor mutational profiling using next generation sequencing after completion of platinum induction can assist in identifying patients with secondary mutations but can be challenging, especially for patients with locally advanced disease and no easily accessible lesions. Identification of acquired resistance mutations in circulating tumor DNA (ctDNA), collected during or after platinum induction, can be helpful. Based on available data, patients with BRCA2 reversion mutations should not be treated with PARPi maintenance; rather, 5-FU maintenance should be selected. For patients with initial benefit on PARPi maintenance, enrollment in trials with novel combinations aiming to bypass resistance, such as ATR or Wee1 inhibitors, should be encouraged.
If maintenance therapy after non-progression on platinum-based therapy remains the right place for PARPi in patients with gBRCA1/2
patients, how can we improve on the results of POLO study? The activation of antitumor immunity with PARPi and the so far documented safety in combination with immune checkpoint inhibitors begs for evaluation after initial induction chemotherapy. A study with niraparib with nivolumab/ipilimumab is currently ongoing (NCT03404960) [103
]. Furthermore, PARPi combinations with MEK or VEGFR inhibitors and or radiotherapy can potentially improve outcomes.