PARP inhibition in treatment of pancreatic cancer
Abstract
Introduction: The landscape of treatment for metastatic pancreatic ductal adenocarcinoma (PDAC), an exceptionally aggressive and challenging malignancy, has seen notable advancements. Specifically, the advent of more effective polychemotherapy regimens has led to improvements in both tumor control and the overall survival rates for affected patients. Despite these incremental gains, there remains an urgent and compelling need for the identification of novel therapeutic targets. Such discoveries are crucial for developing innovative maintenance therapies that can not only sustain tumor control but also significantly enhance patients’ quality of life by reducing the burdens associated with continuous intensive chemotherapy.
Areas covered: A particular subgroup of PDAC, characterized by somatic mutations in homologous recombination repair genes such as *BRCA*, exhibits a distinct and heightened sensitivity to platinum-based chemotherapeutic agents. More recently, the therapeutic potential of poly(ADP-ribose) polymerase (PARP) inhibitors has been actively explored and suggested for this genetically defined subset of patients. A landmark clinical trial, the POLO study, provided compelling evidence in this regard. This study demonstrated that olaparib, a PARP inhibitor, proved to be both efficient and well-tolerated when utilized as a maintenance therapy. Its efficacy was specifically observed in patients with germline *BRCA1/2* mutations and metastatic PDAC, who had achieved disease control following an initial platinum-based induction chemotherapy. This finding represents a significant step forward in personalized medicine for PDAC.
Expert opinion: The unequivocal demonstration of olaparib’s efficacy in patients with metastatic PDAC harboring germline *BRCA* mutations has decisively opened a new therapeutic avenue, paving the way for maintenance strategies that leverage targeted therapy. This success now prompts a series of crucial questions and directions for future research. Further studies are imperatively needed to comprehensively assess several key areas. These include exploring the potential role of PARP inhibitors in earlier forms of PDAC, investigating their utility in patients with somatic *BRCA* mutations or other, rarer “BRCAness” signatures (genomic profiles mimicking *BRCA* deficiency), developing strategies to overcome both primary and acquired secondary resistances to PARP inhibitors, and meticulously evaluating the synergistic potential of combining PARP inhibitors with other established or novel anti-tumor agents. Addressing these areas will be critical for expanding the clinical utility of PARP inhibitors and optimizing therapeutic outcomes for a broader spectrum of PDAC patients.
Keywords: BRCA gene, Cancer, PARP, olaparib, pancreas, PARP inhibitor.
Introduction
Pancreatic ductal adenocarcinoma, commonly referred to as PDAC, stands as a formidable challenge in the global landscape of oncology. It is currently recognized as the thirteenth most prevalent form of cancer worldwide, yet its impact on mortality is disproportionately severe, claiming the seventh position among all cancer-related deaths. The persistently elevated mortality rate associated with pancreatic ductal adenocarcinoma underscores its aggressive nature and the difficulties inherent in its effective treatment. Projections have indicated a concerning trend, suggesting that by the year 2020, the number of fatalities attributable to PDAC was expected to surpass even those caused by colorectal cancer, despite the latter being six times more frequently diagnosed. This stark statistic highlights the critical urgency for advancements in understanding and managing this devastating malignancy.
Historically, the prognosis for patients diagnosed with metastatic PDAC has been particularly grim. However, the introduction of more potent polychemotherapy regimens has offered a glimmer of hope, leading to modest yet significant improvements in patient survival. Regimens such as the combination of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin, collectively known as FOLFIRINOX, or the dual agent therapy of gemcitabine and nab-paclitaxel, have emerged as cornerstone treatments. These intensive chemotherapy approaches are often successful in achieving a degree of tumor control in an increasing proportion of patients, typically observed after an initial treatment phase lasting between four and six months. Furthermore, a considerable subset of these patients, approximately 40% to 50%, may even be eligible to receive a second line of treatment once their disease unfortunately progresses.
Despite these therapeutic advances, the use of intensive polychemotherapies is not without its significant drawbacks. Patients frequently experience a range of severe and problematic toxicities, which can profoundly impact their overall quality of life. Among the most concerning are cumulative neurotoxicity, which can manifest as persistent nerve damage, and debilitating diarrhea. Such adverse events often necessitate a reduction in the intensity of the treatment regimen following an initial induction phase. This clinical reality underscores the vital need for carefully designed maintenance therapy options, which aim to sustain tumor control while simultaneously mitigating treatment-related toxicities. In response to this crucial unmet need, the prospective phase II PRODIGE 35-PANOPTIMOX study was meticulously conducted. This pivotal trial sought to compare the efficacy and safety of administering leucovorin-5-FU (LV5FU2) as a maintenance therapy for patients whose metastatic PDAC had achieved control after a four-month course of FOLFIRINOX. The study’s findings were then juxtaposed against the outcomes observed when patients either continued with the full, triple-combination FOLFIRINOX regimen or transitioned to a 5-FU-irinotecan combination, known as FOLFIRI-3. While the results indicated that maintenance with LV5FU2 yielded similar levels of tumor control compared to the continued triple combination, a notable and concerning finding was the higher rate of severe neurotoxicity observed in the maintenance therapy arm. This was largely attributed to the fact that patients in this group likely received a higher cumulative dosage of oxaliplatin over time, highlighting the delicate balance between efficacy and managing treatment-related side effects.
Unmet Needs of Currently Available Therapies in Advanced PDAC
The therapeutic landscape for advanced pancreatic ductal adenocarcinoma continues to be marked by substantial unmet needs, reflecting the inherent challenges posed by this aggressive and often recalcitrant malignancy. Despite decades of intensive research, the arsenal of highly effective systemic treatments remains critically limited. In fact, robust clinical evidence has demonstrated the superiority of only two specific chemotherapy combinations when compared to gemcitabine monotherapy, which had long served as a standard but often insufficient treatment option. This scarcity of truly impactful first-line agents underscores the urgency for novel therapeutic strategies.
Beyond conventional chemotherapy, the development and application of targeted therapies in advanced PDAC have largely been fraught with difficulties. While these agents have revolutionized treatment paradigms in numerous other cancers by specifically interfering with molecular pathways crucial for tumor growth and survival, most targeted therapies rigorously tested in the induction phase for advanced PDAC have, unfortunately, yielded disappointing results to date. This consistent pattern of failure highlights the intricate and often redundant signaling networks within pancreatic cancer cells, as well as the protective influence of the dense tumor microenvironment.
Intensive research endeavors are, however, relentlessly pursuing new avenues by focusing on the specific genetic mutations and molecular aberrations that drive the pathogenesis of this tumor. For instance, the infamous KRAS mutation, a common and notoriously challenging oncogene in PDAC, is being targeted through various innovative approaches, including direct KRAS inhibitors, therapeutic vaccines designed to stimulate an immune response against KRAS-mutated cells, specific antibodies, and downstream MEK inhibitors. Similarly, efforts are underway to address other critical molecular players: CDKN2A, a cell cycle regulator, is being targeted by CDK4 and CDK6 inhibitors; SMAD signaling pathways, often disrupted in PDAC, are the focus of TGF inhibitors; BRAF mutations, though less common than KRAS, are being pursued with BRAF and MEK inhibitors; microsatellite instability (MSI), indicative of DNA repair defects, can render tumors susceptible to anti-PD-1 immunotherapies like pembrolizumab; NRG1 gene fusions are being explored with EGF inhibitors such as afatinib or pertuzumab; NTRK gene fusions are targeted by larotrectinib; and ALK amplifications are being investigated with crizotinib. Each of these represents a distinct molecular vulnerability, and the goal is to precisely tailor therapies to the unique genetic fingerprint of an individual patient’s tumor.
In addition to these specific oncogenic drivers, a particularly promising area of research revolves around tumors that exhibit abnormalities in homologous recombination repair (HRR) genes. This critical DNA repair pathway, which involves genes such as BRCA1, BRCA2, PALB2, or ATM, is essential for accurately repairing potentially catastrophic double-strand breaks in DNA. When these genes are mutated or otherwise dysfunctional, the cell’s ability to repair stalled replication forks is severely compromised, rendering these tumor cells exquisitely sensitive to a class of drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). The emerging role of PARP inhibitors, particularly in the maintenance setting for patients who have achieved a significant decrease in tumor burden following initial induction chemotherapy, merits comprehensive and rigorous further assessment. Within this evolving context, the judicious utilization of PARP inhibitors is paving a crucial new therapeutic pathway, offering a tailored treatment option for a specific subset of PDAC patients whose tumors harbor BRCA gene mutations or other related homologous recombination deficiencies.
PARP Inhibitors: Pharmacodynamics, Pharmacokinetics and Metabolism
The integrity of the genetic material within a normal cell is meticulously maintained through a complex and highly coordinated network of DNA damage repair (DDR) pathways. This sophisticated cellular machinery acts as a vigilant guardian, constantly monitoring for and correcting various forms of DNA damage to prevent mutations and maintain genomic stability. Among the principal pathways involved are nucleotide excision repair (NER), base-excision repair (BER), mismatch repair (MMR), the high-fidelity homologous recombination (HR) repair, and the more error-prone non-homologous end joining (NHEJ). Of particular significance, double-strand breaks (DSBs) represent one of the most perilous forms of DNA damage, capable of causing genomic instability and cell death if not properly repaired. These critical lesions are primarily managed by two distinct pathways: the precise homologous recombination and the expedient, though less accurate, non-homologous end joining.
Within this intricate DDR network, poly(ADP-ribose) polymerase 1 (PARP1) stands out as a pivotal actor, particularly within the base-excision repair pathway. PARP1 is a central member of the extensive PARP protein superfamily, which in mammals encompasses an impressive array of eighteen distinct members. While these proteins are encoded by different genes, they share a conserved catalytic domain, which is fundamental to their enzymatic function. PARP-1 itself is a substantial 113 kDa protein, intricately organized into seven independent functional domains. Its N-terminus region contains a specific nuclear localization sequence, which precisely directs PARP-1 to its operational site within the nucleus. This region also harbors the Zn1, Zn3, and WGR domains, which are instrumental in recognizing and binding to sites of DNA damage. Upon recognizing such damage, an allosteric activation mechanism is triggered, dramatically stimulating PARP-1’s catalytic activity. This activity involves the consumption of nicotinamide adenine dinucleotide (NAD+) to synthesize long, branched polymers of polyADP-ribose (pADPr). This process, known as autoPARylation, sees pADPr attached to PARP-1 itself, as well as to various histone proteins and other chromatin-associated factors.
The newly synthesized pADPr polymers then serve as critical signaling platforms, recruiting a host of other DNA repair proteins, such as XRCC1, to the site of damage. PARP-1 also plays a direct role in recruiting proteins essential for the homologous recombination pathway, including ATM, Drc11, and NSB1. Subsequently, this process of PARylation, which involves the transfer of ADP-ribose residues to target substrates by ADP-ribosyl transferases using NAD+ as a donor, ultimately reduces the affinity of PARP-1 for the DNA. The pADPr polymers are then swiftly removed from PARP-1 by specific enzymes, poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosyl-acceptor hydrolase 3 (ARH3). This precise removal of PARP-1 through autoPARylation is crucial, as it then allows other essential DDR proteins, such as DNA polymerase and DNA ligase III, to access the DNA and complete the repair process. Furthermore, PARP-1 is known to activate ATM and the NHEJ pathway; consequently, a deficiency in ATM, a crucial kinase in DNA damage response, is expected to sensitize PDAC cells to the effects of PARP inhibitors. Early studies in PARP knockout mice, specifically those lacking PARP proteins (-/-), provided foundational insights, revealing that these proteins play a significant role in mediating resistance to certain alkylating agents, thereby underscoring their importance in cellular defense mechanisms.
The therapeutic utility of PARP inhibitors stems from their ability to selectively destroy tumor cells through two principal mechanisms: synthetic lethality or a process known as PARP trapping. The strategic application of PARP inhibitors has already achieved significant success in the treatment of gynecologic and prostate cancers, and is now extending its reach into pancreatic cancer, serving as a prime example of this innovative therapeutic approach. Genomic sequencing efforts, specifically whole-genome sequencing of PDAC tumors, have provided invaluable insights into their molecular heterogeneity. These analyses have led to a classification of PDAC into distinct subtypes based on variations in chromosomal structures: ‘stable,’ ‘locally rearranged,’ ‘scattered,’ or ‘unstable.’ Intriguingly, the ‘unstable’ genotype was identified in approximately 14% of PDAC cases. This subtype was characterized by a profusion of structural variations within the genome, strongly suggesting underlying defects in critical DNA repair pathways, and importantly, exhibiting a distinctive ‘BRCA mutational signature.’
The presence of defects in double-strand break (DSB) repair or mismatch repair within canonical homologous recombination genes, such as BRCA1 and BRCA2, has been consistently associated with an increased expression of antitumor immunity. This enhanced immune response is characterized by the activation and proliferation of CD8-positive T lymphocytes, key effectors of adaptive immunity, as well as an overexpression of crucial regulatory molecules like cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed death-ligand 1 (PD-L1). This immunological activation is directly linked to a higher frequency of somatic mutations within the tumor genome and the consequent production of tumor-specific neoantigens, which serve as potent targets for the immune system. A germline mutation in the BRCA genes (gBRCAm) is found in a notable proportion of patients with PDAC, estimated to be between 5% and 7%. Beyond germline alterations, somatic mutations can also occur in a broader spectrum of genes involved in DNA repair, including not only BRCA2 and BRCA1 but also PALB2, ATM, and RAD51, among others. With this expanded understanding of DSB repair deficient genes, it is now recognized that up to 15% of PDAC tumors carry what is referred to as a ‘BRCAness’ signature, indicating a functional deficiency in homologous recombination, irrespective of whether a germline BRCA mutation is present. Patients diagnosed with breast and ovarian cancers who harbor a gBRCAm are particularly sensitive to platinum-based chemotherapies, as well as to PARP inhibitors such as olaparib. Both of these drug classes adeptly exploit the inherent homologous recombination deficiencies in BRCA1/2-deficient tumor cells, leading to the devastating phenomenon of synthetic lethality, where the combined effect of two non-lethal events results in cell death.
Building upon this profound understanding of synthetic lethality, the PARP inhibitor olaparib has already gained significant clinical traction and regulatory approval for its use in other malignancies. It is approved as a maintenance therapy for patients with ovarian cancer who have achieved either a complete or partial response to prior platinum-based chemotherapy. Furthermore, olaparib is also sanctioned as a monotherapy for patients with a confirmed gBRCAm and advanced ovarian cancer or HER2-negative breast cancer. These established precedents in related cancers underscore the immense potential of PARP inhibitors in harnessing the molecular vulnerabilities of tumors with homologous recombination deficiencies.
Clinical Efficacy of PARPi in PDAC
The therapeutic landscape of PARP inhibitors has expanded considerably with the availability of six distinct molecules: olaparib, rucaparib, veliparib, niraparib, talazoparib, and pamiparib. While each agent possesses unique pharmacokinetic properties, their primary mechanism of action converges on the inhibition of both PARP-1 and PARP-2 enzymes. The critical cytotoxic effect of PARP inhibitors is largely attributed to their capacity to “trap” PARP-1 on the DNA at sites of single-strand breaks. This trapping mechanism prevents the release of PARP-1 and, crucially, blocks the recruitment of essential DNA repair proteins, leading to the formation of highly cytotoxic DNA-PARP complexes. These complexes act as roadblocks, impeding DNA replication forks and ultimately leading to the accumulation of lethal double-strand breaks, particularly in cells that already possess underlying defects in homologous recombination repair. At a molecular level, PARP inhibitors achieve this by forming strong interactions; they typically possess a carboxamide group that forms hydrogen bonds with the serine hydroxyl and glycine residues within the nicotinamide adenine dinucleotide (NAD+) binding pocket of the PARP enzymes, effectively outcompeting NAD+ and inhibiting PARP’s catalytic activity. Furthermore, PARP-1 is known to block non-homologous end joining (NHEJ) by PARylating key subunits such as Ku 70/80 and DNA-PKcs. In addition, PARP-1 induces PARylation of the RING domain linked to BRCA1-associated RING domain protein 1 (BARD-1) prior to the double-strand break resection and subsequent combination with RAD51, which is of paramount importance for the homologous recombination repair pathway in normal cells. Research has indicated that BGL3 binds BARD1 and plays a role in mediating the retention of the BRCA1/BARD1 complex, along with binding partners like HP1γ and RAD51, at sites of DNA damage, thereby controlling the critical process of DNA end resection.
Despite the well-established efficacy of PARP inhibitors in breast and ovarian cancers, the existing literature investigating the effectiveness of these agents in eligible patients with pancreatic ductal adenocarcinoma remains comparatively limited. Much of the early evidence in PDAC has been derived from isolated case reports or smaller-scale phase I and II studies, which, while suggestive of potential benefit, often lack the statistical power and comprehensive design of larger trials. To date, only one pivotal phase III trial, known as the POLO study, has been published, serving as a landmark investigation into the utility of PARP inhibitors in this challenging disease.
Olaparib in the POLO study
The foundational concept for utilizing PARP inhibitors in pancreatic ductal adenocarcinoma was initially suggested in 2015 by the exploratory phase II trial conducted by Kaufman and colleagues. This seminal study provided early, promising insights by administering olaparib monotherapy to patients with germline BRCA-mutated (gBRCAm) PDAC who had been heavily pretreated with one to eight lines of prior chemotherapy. The results were indeed encouraging, demonstrating a respectable response rate of 21.7%, a progression-free survival (PFS) of 4.6 months, and an overall survival (OS) of 9.8 months. These compelling preliminary findings served as the impetus for the design and execution of the phase III POLO trial, a comprehensive study conceived to prospectively and rigorously evaluate the efficacy of olaparib in a larger patient population.
The POLO study embarked on an extensive screening process, initially testing patients with sporadic metastatic PDAC from diverse geographic regions and continents for their germline BRCA mutation status, which was largely unknown at the outset. Out of a total of 2167 patients screened, 128 individuals, representing 5.9% of the cohort, were identified as having a newly detected gBRCAm. When including patients with previously known mutations, the POLO study ultimately enrolled a total of 159 patients, or 7.2% of the screened population, who harbored a gBRCAm. Within this cohort, BRCA2 mutations accounted for approximately 70% of cases, while BRCA1 mutations constituted the remaining 30%. Interestingly, some geographic variations in the prevalence of these mutations were observed. Furthermore, patients with gBRCAm in this study tended to be younger, with a median age of 57.9 years, compared to 61.1 years in patients without gBRCAm, hinting at potential biological or hereditary distinctions.
Following this meticulous screening, from the 3315 patients initially assessed in the broader POLO study, 154 gBRCAm patients who had achieved disease control after at least 16 weeks of platinum-based induction chemotherapy were ultimately randomized. The induction regimens predominantly included FOLFIRINOX variants (n = 129), with a smaller number receiving gemcitabine-cisplatin (n = 5) or other regimens (n = 18), and two cases with missing data. It is noteworthy that approximately one-third of these patients had received induction chemotherapy for longer than six months. These eligible patients were then randomly assigned to receive either olaparib (92 patients) or a placebo (62 patients) as maintenance therapy. The primary endpoint of the study, progression-free survival, was successfully met, demonstrating a statistically significant and clinically meaningful advantage for the olaparib arm. The median PFS in the olaparib group was 7.4 months, remarkably superior to the 3.8 months observed in the placebo arm, yielding a hazard ratio of 0.53 (with a 95% confidence interval of 0.35 to 0.82) and a highly significant p-value of 0.004.
While the efficacy data were compelling, the safety profile of olaparib also received careful scrutiny. The rate of grade ≥3 adverse events was higher in the olaparib group at 39.6%, compared to 23.3% in the placebo arm. Discontinuation of treatment due to an adverse event occurred in 5.5% of olaparib-treated patients versus 1.7% in the placebo arm. A crucial aspect of maintenance therapies in PDAC is the preservation or improvement of the patient’s quality of life (QoL). Encouragingly, the study found that QoL was not adversely impacted in patients receiving olaparib when compared to those on placebo. However, one notable finding was the absence of a statistically significant difference in overall survival (OS) between the two treatment groups. Several plausible explanations have been put forth to account for this observation. Firstly, the OS results were based on an interim analysis, which captured only 46% maturity of the data, with the final analysis planned at a higher maturity level of 69%. This suggests that the full picture of OS benefit may not have been captured at the time of the analysis. Secondly, the OS results were likely influenced by the subsequent treatments administered to patients after tumor progression.
Patients in the placebo arm, upon disease progression, would often have been retreated with agents that remained potentially effective given their BRCAm status, such as platinum agents and/or irinotecan, potentially confounding the OS comparison. Thirdly, and critically, it was revealed that by the time of the ASCO meeting in June 2019, nine patients (15%) from the placebo arm had, in fact, received a PARP inhibitor following tumor progression, despite cross-over not being permitted by the study protocol. Such off-protocol treatments could further dilute any potential OS benefit attributable to olaparib. It is also important to consider that median OS may not fully encapsulate the duration of sustained responses. In this regard, the duration of sustained responses was considerably longer in the olaparib arm, averaging 24 months, compared to a mere 3.7 months in the placebo arm, indicating a prolonged period of disease control for a subset of patients. Further analysis involving Progression-Free Survival 2 (PFS2), which measures the time from randomization to progression on the treatment administered after the protocol-mandated discontinuation of study treatment or death, suggested that treatment with olaparib preserved the benefit of post-protocol therapy. The median PFS2 was 13.2 months in the olaparib arm versus 9.2 months in the placebo arm (HR, 0.76; 95% CI, 0.46 to 1.23; P=0.26), suggesting that olaparib did not compromise the effectiveness of subsequent treatments.
The promising results from the POLO study have opened new avenues for future research. Further investigations are necessary to determine the optimal role of olaparib and other PARP inhibitors in different clinical settings, such as in non-metastatic PDAC, as an adjuvant therapy following surgical resection, or in combination with other induction chemotherapies beyond platinum agents, such as the gemcitabine-nab-paclitaxel combination. Building on these pivotal findings, on December 27, 2019, the Food and Drug Administration (FDA) granted approval for olaparib as a maintenance treatment for adult patients with deleterious or suspected deleterious gBRCAm metastatic PDAC. This approval, based on detection by an FDA-approved test, is specifically for patients whose disease has not progressed after at least 16 weeks of a first-line platinum-based chemotherapy regimen, marking a significant milestone in the targeted treatment of pancreatic cancer.
Combinations of PARPi with Other Agents
The pursuit of enhanced therapeutic efficacy and the overcoming of intrinsic or acquired resistance mechanisms in pancreatic ductal adenocarcinoma have led to intensive research into combination strategies involving PARP inhibitors with various other anticancer agents. One of the most intuitively appealing combinations involves PARP inhibitors and platinum-based chemotherapeutic agents. The rationale for this synergy lies in the fact that platinum compounds exert their cytotoxic effects primarily by inducing DNA damage, particularly inter-strand crosslinks, which then necessitate robust DNA repair pathways for cellular survival. By simultaneously inhibiting PARP, a key player in DNA repair, the tumor cells become exceptionally vulnerable, as their compromised repair capabilities are further overwhelmed by platinum-induced damage.
Among the PARP inhibitors, veliparib has been extensively studied, particularly in gynecologic cancers, due to its relatively lower “trapping” ability compared to some other PARP inhibitors. This characteristic theoretically suggested it might be more amenable to combination with DNA-damaging agents, potentially offering a more favorable safety profile while still enhancing efficacy. In a noteworthy study conducted by O’Reilly and colleagues, 50 patients with gBRCA or PALB2 mutated PDAC were randomized to receive either a combination of gemcitabine (600 mg/m2) and cisplatin (25 mg/m2) on days 3 and 10 alone, or the same chemotherapy regimen augmented with oral veliparib at a dose of 80 mg twice daily from day 1 to day 12, with cycles administered every three weeks. Interestingly, the response rate in the arm that included veliparib was not found to be superior to the chemotherapy-alone arm, with response rates of 74.1% and 65.2% respectively (P = 0.55). Similarly, there were no significant improvements in median progression-free survival (10.1 months in the chemotherapy-alone arm versus 9.7 months with veliparib, P = 0.73) or median overall survival (15.5 months versus 16.4 months, P = 0.6).
Overall, the addition of veliparib did not enhance the clinical outcomes and, notably, was associated with an increased incidence of grade 3–4 hematological toxicity. However, the study did underscore the valuable efficacy of the gemcitabine-cisplatin combination itself in this specific patient population. In contrast, another study by Binder et al. provided more encouraging results for a combination approach, reporting that a maintenance therapy combining rucaparib and platinum in PDAC patients with germline gBRCA/PALB2 mutations yielded an interesting progression-free survival of 9 months and an overall response rate of 36.8%, with six patients achieving a partial response and one even reaching a complete response. These divergent findings highlight the potential differences in the pharmacological profiles of individual PARP inhibitors and the importance of specific patient selection. Martino et al. also suggested that the sequential administration of platinum-based chemotherapy followed by PARP inhibitors might be less effective in tumors harboring ATM mutations compared to those with BRCA and PALB2 mutations, indicating a need for refined patient stratification.
Beyond platinum agents, alkylating agents such as temozolomide, or topoisomerase inhibitors, have also been investigated in combination with PARP inhibitors in other cancer types, including melanoma and colorectal cancer. However, the combination of PARP inhibitors with any DNA-damaging chemotherapy agents necessitates extremely careful monitoring for potential toxicities. For instance, while the tolerance of combining PARP inhibitors with paclitaxel or gemcitabine generally appears acceptable, a significant increase in hematologic toxicity has been observed when olaparib was combined with more potent DNA-damaging agents like cisplatin or irinotecan. This underscores the critical need for meticulous dose optimization and vigilant patient management in such combination regimens.
Another intriguing combination strategy involves PARP inhibitors with anti-angiogenic drugs, such as cediranib or bevacizumab. This approach is predicated on exploiting the observation that the hypoxic microenvironment, which is characteristic of many solid tumors including PDAC, can lead to reduced expression of DNA repair proteins like BRCA1 and RAD51C. This hypoxia-induced deficiency in homologous recombination renders tumor cells more susceptible to PARP inhibition, creating a synergistic effect with anti-angiogenic agents that aim to normalize the tumor vasculature and alleviate hypoxia.
Perhaps one of the most exciting and rapidly evolving areas of combination therapy research involves PARP inhibitors with immune checkpoint inhibitors, specifically anti-PD-1 agents such as avelumab, atezolizumab, durvalumab, nivolumab, or pembrolizumab. The rationale underpinning this combination is multifaceted and compelling. Firstly, homologous recombination deficiency, particularly when compensated by the more error-prone non-homologous end joining pathway, inevitably leads to the accumulation of somatic mutations and widespread genomic instability within tumor cells. This genetic chaos results in the production of a high burden of tumor-specific neoantigens, which are then recognized by the immune system and can drive T-cell activation. Secondly, the accumulation of cytosolic DNA fragments, a direct consequence of defective DNA repair pathways, can activate the innate immune system through the cGAS-STING pathway. This pathway initiates an inflammatory response, leading to the production of interferons and other cytokines that can recruit and activate immune cells within the tumor microenvironment.
Furthermore, studies have demonstrated that PARP inhibitors can upregulate the expression of PD-L1 in breast cancer cell lines and animal models, potentially through the inactivation of GSK3β. This upregulation of PD-L1 initially suggested a mechanism of resistance, but paradoxically, PARP inhibitor-attenuated anticancer immunity via PD-L1 upregulation on tumor cells can resensitize them to T-cell killing, setting the stage for effective immunotherapy. Adding further weight to this hypothesis, Seeber and colleagues reported that advanced PDAC tumors with BRCA mutations were significantly associated with a higher frequency of microsatellite instability-high (MSI-H) (4.8% vs. 1.2%, p = 0.002), elevated PD-L1 expression (22% vs. 11%, p < 0.001), and a higher tumor mutational burden (mean 8.7 mutations per megabase vs. 6.5, p < 0.001). These robust findings provide strong encouragement for rigorously testing combinations of PARP inhibitors with immunotherapy in patients with BRCA-mutant PDAC, including those tumors that are microsatellite stable (MSS) but still exhibit homologous recombination deficiencies. The broader field of DNA damage repair also remains a fertile ground for further combination strategies, with ongoing investigations exploring inhibitors of other critical DDR proteins, such as ATR, Chk1, wee1, and PI3K, to further enhance the cytotoxic effects on cancer cells. Moreover, epigenetic modifiers like Bromodomain and Extraterminal (BET) inhibitors, such as JQ1, are being explored for their potential to sensitize tumors to PARP inhibitors through the inhibition of BRD4 and BRD2-dependent expression of key repair proteins like RAD51 (involved in HR) and Ku80 (involved in NHEJ), thereby creating additional vulnerabilities for therapeutic exploitation. PARP Inhibitors in Development The ongoing efforts to expand therapeutic options for advanced pancreatic ductal adenocarcinoma (PDAC) include a robust pipeline of phase II clinical studies focused on evaluating the efficacy of PARP inhibitors (PARPi). These studies, widely registered on platforms like ClinicalTrials.gov, are meticulously designed to explore various applications and combinations of PARPi, aiming to broaden their utility beyond the established indications. In one such promising study, olaparib, an already approved PARPi, is being investigated in patients who do not harbor a germline BRCA1/2 mutation but possess either a compelling family history indicative of hereditary cancer risk or evidence of somatic BRCAness in their tumors (NCT02677038). This approach seeks to identify a wider cohort of patients who might benefit from PARP inhibition based on a functional deficiency in DNA repair, rather than solely relying on germline mutations. Another innovative trial is evaluating the ATR kinase inhibitor AZD6738, both as a single agent and in combination with olaparib. This study incorporates a fascinating stratification strategy, tailoring the treatment arms according to the status of BAF250a, a protein encoded by the ARID1A gene, to explore potential biomarkers of response (NCT03682289). Furthermore, the synergistic potential of combining olaparib with cediranib, a multi-targeted tyrosine kinase inhibitor that blocks VEGFR-2, platelet-derived growth factor receptor (PDGFR), and c-kit, is being assessed in patients with various solid tumors, including PDAC (NCT02498613). This combination aims to exploit the interplay between DNA repair pathways and angiogenesis. Niraparib, another prominent PARPi, is also undergoing extensive investigation. Its efficacy is being tested in patients with either germline or somatic mutations in various DNA repair genes (NCT03601923). Additionally, in the NIRA-PANC study, niraparib is being evaluated specifically after the administration of platinum-based chemotherapy in patients with germline or somatic BRCAness mutations, aiming to establish its role in a maintenance setting for this sensitive population (NCT03553004). Expanding its reach into immunooncology, niraparib is also being combined with the anti-CTLA4 antibody ipilimumab or the anti-PD-1 antibody nivolumab as maintenance therapy in the PARVAX study. This specific trial targets patients whose tumors have achieved control following platinum-based chemotherapy, leveraging the hypothesis of synergy between DNA damage repair inhibition and immune checkpoint blockade (NCT03404960). Rucaparib, a third PARPi, is likewise being assessed for its efficacy. It is being evaluated as maintenance therapy in patients with BRCA1/2 or PALB mutations (NCT03140670). In a broader context, rucaparib is also included in the LODESTAR study, which assesses patients with various solid tumors exhibiting deleterious mutations in homologous recombination repair (HRR) genes, with a specific focus on differentiating outcomes between BRCA1/2 mutations and other HRR gene alterations (NCT04171700). Beyond the metastatic setting, research is also extending into earlier stages of the disease. In patients with resectable PDAC, a phase II study has been designed to compare pre-treatment biopsies with post-treatment resection specimens. This study aims to identify novel biomarkers of response or resistance in patients who have received either a MEK inhibitor (cometinib) or olaparib, providing valuable insights into the biological impact of these agents in the neoadjuvant setting (NCT04005690). Finally, the landscape of PARP inhibitors in development includes two early-phase studies (phase I or Ib/II) exploring a novel PARPi, NMS-03305293, as a single agent in gBRCAm patients with solid tumors, including PDAC, with a focus on dose escalation (NCT04182516). Another study is investigating a combination regimen of fluzoparib plus modified FOLFIRINOX (mFOLFIRINOX), followed by fluzoparib (SHR-3162) as maintenance therapy in patients with gBRCA1/2 or PALB2 mutations (NCT04228601). In a concerted effort to further advance the field, the PRODIGE-GERCOR group has meticulously designed the MAZEPPA randomized phase II study (EUDRACT No.: 2019–004366-18). This innovative trial is set to evaluate, in patients with metastatic PDAC whose disease has been controlled after FOLFIRINOX induction, a tailored maintenance therapy. Patients will be randomized to receive either olaparib or a combination of selumetinib (a MEK 1/2 inhibitor) plus durvalumab (an anti-PDL-1 antibody), with treatment assignment guided by the individual patient’s BRCAness and KRAS somatic status. This stratified approach represents a significant step towards personalized medicine in PDAC. Mechanisms of Resistance to PARPi The emergence of resistance to PARP inhibitors (PARPi) represents a significant hurdle in cancer therapy, particularly in the context of prolonged treatment. Consequently, understanding and overcoming this phenomenon is a matter of intensive and ongoing research. The complexity of tumor cell biology allows for a multitude of mechanisms through which resistance can manifest, rendering previously effective PARPi treatments ineffectual. One of the most well-documented and clinically relevant mechanisms involves the restoration of the open reading frame of mutated BRCA1/2 alleles. This phenomenon occurs when secondary reversion mutations arise within the tumor cells, often under the selective pressure exerted by PARPi or platinum-based chemotherapy. These reversion mutations can be single base substitutions, or insertions/deletions that occur in close proximity to the initial protein-truncating mutation. The remarkable consequence of these secondary mutations is that they effectively "correct" the original genetic defect, leading to the production of a wild-type, functional, full-length BRCA protein. When a functional BRCA protein is re-established, the deficient homologous recombination (HR) repair pathway, which was the Achilles' heel exploited by PARP inhibitors, regains its proficiency. This restoration of HR proficiency allows tumor cells to efficiently repair DNA damage, thereby nullifying the synthetic lethality effect of PARP inhibitors and leading to drug resistance. Beyond direct restoration of HR function, tumor cells can also acquire other protective mechanisms that confer resistance to PARP inhibitors. For example, some resistant cells develop an enhanced ability to protect their replication forks, which are highly vulnerable structures during DNA replication. This protection can be achieved through various means, such as the upregulation of alternative DNA repair pathways, specifically the ATR/CHK1 pathway, which helps to stabilize and restart stalled replication forks. Another critical mechanism involves the restoration of RAD51 foci formation. RAD51 is a central protein in homologous recombination, and its ability to form nuclear foci at sites of DNA damage is indicative of active and functional HR. If tumor cells, through various genetic or epigenetic adaptations, can restore RAD51 foci formation, they effectively circumvent the PARPi-induced blockade of HR, thus developing resistance. It is also important to differentiate the influence of somatic reversion mutations on therapeutic impact from those detected in circulating cell-free DNA (cfDNA), which offers a more comprehensive reflection of the global tumor mutational landscape. Consequently, the analysis of circulating cell-free DNA for the presence of BRCA reversion mutations holds immense promise for guiding treatment decisions in the future. This non-invasive approach could potentially allow clinicians to identify patients who are likely to be resistant to PARPi even before treatment initiation, or to monitor for the emergence of resistance during therapy. Evidence suggests that reversion mutations contribute not only to acquired resistance, which develops after an initial period of response, but also to primary resistance, where tumors fail to respond to treatment from the outset. For instance, a study by Lin and colleagues detected BRCA reversion mutations in circulating cell-free DNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant high-grade ovarian cancers, even before rucaparib administration. This contrasts sharply with their detection in only 2% (1/48) of platinum-sensitive cancers (P = 0.049), suggesting that these pre-existing reversion mutations predict initial treatment failure. Furthermore, patients without pretreatment BRCA reversion mutations experienced significantly longer progression-free survival (9.0 months vs. 1.8 months; HR, 0.12; P < 0.0001), reinforcing the prognostic value of these mutations. The study also found BRCA reversion mutations in 8 out of 78 additional patients who subsequently developed acquired resistance to rucaparib, solidifying their role in both primary and acquired resistance. In the POLO study, which evaluated olaparib in PDAC, a notable 40% of patients who received olaparib experienced early tumor progression, defined as progression within four months of starting therapy. This significant proportion points towards a substantial rate of primary resistance to the drug. Therefore, a critical area of ongoing research involves precisely identifying the factors and underlying mechanisms associated with such early treatment failure to PARP inhibitors. A more thorough understanding of these determinants will be instrumental in optimizing patient selection and refining administration strategies to maximize the therapeutic benefit of PARP inhibitors in PDAC. Other mechanisms of resistance include mutations in the BRCA1 C-terminal domain, BRCA1 reactivation through epigenetic regulation, such as the reversion of hypermethylation, stabilization or prolonged stalling of replication forks through deficiencies of MLL3/4 in BRCA2 mutant cells, which reduces the activity of nuclease MRE11 and decreases MUS81 recruitment, or the loss of Pax2 transactivation domain interacting protein (PTIP) or SLFN11. The presence of a hydromorphic BRCA1 or 2 allele, demethylation of the BRCA1 promoter, or specific BRCA1-C61G mutation disrupting the N-terminal RING domain can also contribute to resistance. Furthermore, stabilization of the BRCT domain by HSP90, interactions with the PALB2-BRCA2-RAD51 complex leading to the formation of RAD51 foci, or the loss of PARP-1 expression or mutations like 1771 C > T, as well as a decrease in PARP-1 levels during tumor development, have been implicated. Alterations in miR-622 can divert DNA repair towards the HR pathway while suppressing NHEJ via Ku complexes, thereby modulating the NHEJ pathway and desensitizing BRCA1-proficient cells to PARP inhibitors. The loss of p53-binding protein 1 (53BP1) can lead to an imbalance between error-free HRR and downregulated NHEJ. Reversion of HR defects in BRCA1 deficient cells, often through the loss of end resection regulation involving PTIP, RIF1, REV7, RINN1 (SHLD3), RINN2 (SHDL2), and RINN3 (SHLD1), can also restore HR functionality. An increase in RAD51 protein at stalled forks and enhanced PALB2-BRCA2 recruitment to DNA breaks, dependent on ATR, further contribute. Finally, the lack of poly(ADP-ribose) glycohydrolase (PARG) leading to restoration of PARylation, dysregulation of drug-efflux transporter genes like multi-drug resistance protein 1 (MDR1) with increased P-glycoprotein efflux of PARPi, overexpression of ATP-binding cassette (ABC) ABCB1 a/b (reversible by verapamil or elacridar), overexpression of the HOX family, and deregulation of kinases such as MET, EGFR, VEGFR, and AXL, exemplified by MET phosphorylation of PARP-1 at Tyr 907, are all factors that can mediate PARP inhibitor resistance.
Conclusions
The POLO study stands as a landmark achievement in the field of pancreatic ductal adenocarcinoma (PDAC) treatment. It represents the first unequivocal demonstration of the significant value of targeted therapy specifically for a defined, albeit small, subset of PDAC patients who harbor germline BRCA mutations. This pivotal trial has not only opened new therapeutic avenues but has also profoundly reshaped the treatment paradigm for this aggressive disease.
Looking ahead, future research endeavors will focus on several critical areas to further expand the utility of PARP inhibitors (PARPi). These include assessing the efficacy of PARPi in earlier forms of PDAC, such as in the neoadjuvant or adjuvant settings, where they could potentially improve surgical outcomes or prevent recurrence. Furthermore, studies will explore their value in patients with rarer BRCAness signatures or other somatic actionable mutations in key DNA repair genes, such as ATM, PALB2, CHEK1/2, and ATR. A concerted effort will also be directed towards understanding and overcoming the various mechanisms of resistance that can develop during PARPi treatment. This will involve designing innovative combinations of PARPi with other antitumoral agents, aiming for synergistic effects that could enhance efficacy and circumvent resistance pathways.
In light of the evolving understanding of hereditary cancer risk in PDAC, the recent ASCO Provisional Clinical Opinion on this topic provides crucial guidance. It strongly recommends a comprehensive review of the family history of cancer for all patients diagnosed with PDAC. Furthermore, it advises that germline genetic testing for cancer susceptibility should be discussed with individuals diagnosed with pancreatic cancer, even in cases where the family history appears unremarkable. These recommendations underscore the growing recognition of the genetic underpinnings of PDAC and the importance of identifying patients who may benefit from targeted therapies like PARP inhibitors. Correspondingly, ASCO guidelines concerning metastatic PDAC and BRCA mutations have also been recently updated to reflect these significant advancements and recommendations.
Expert Opinion
The seminal demonstration of olaparib’s efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who possess a germline BRCA mutation, as evidenced by the POLO study, has undoubtedly marked a transformative moment in the management of this challenging disease. This finding has now firmly established a new paradigm, paving a clear pathway for the integration of targeted therapy into the maintenance treatment landscape for this specific patient population.
However, despite this significant breakthrough, it is crucial to acknowledge that the cohort of PDAC patients currently eligible to benefit from a PARP inhibitor remains relatively limited. To maximize the therapeutic potential of these agents, there is an imperative need to expand the assessment of PARP inhibitors beyond germline BRCA mutations. This expansion should rigorously evaluate their role in patients whose tumors harbor somatic mutations in BRCA genes, as well as those with other, more rare germline mutations associated with the broader spectrum of BRCAness. Concurrently, the precise role of routine genetic testing for BRCAness mutations in patients with sporadic PDAC, meaning those without an obvious familial link, warrants thorough and comprehensive further assessment. Such widespread testing could potentially identify a larger group of patients who could derive benefit from PARP inhibition.
Furthermore, the utility of PARP inhibitors should not be confined solely to the metastatic setting. It is critically important for these agents to be rigorously tested in earlier forms of PDAC that carry BRCA mutations, as well as in patients who have been treated with non-platinum-based induction chemotherapies. This broader application could potentially lead to improved outcomes in various stages of the disease. Beyond initial treatment, extensive further investigation is warranted for combinations of PARP inhibitors with other antitumoral agents, aiming to enhance efficacy, overcome resistance, Stenoparib and broaden their applicability. Equally vital is the exploration of therapeutic strategies for PDAC that has regrettably become resistant to a PARP inhibitor, necessitating alternative approaches. Ultimately, advancements in our understanding of PARP inhibitors in PDAC will be greatly propelled by the wealth of experience and knowledge continuously accumulated from their successful and evolving application in the treatment of gynecological and prostatic cancers that also exhibit abnormalities in homologous recombination repair pathways.