Utilizing therapeutic response as a criterion for PARP inhibitor maintenance therapy in advanced triple negative breast cancer; promoting personalized medicine

A driving principle in oncologic research is the identification of oncogenic molecular targets to offer personalized treatment of cancer, a concept broadly known as precision oncology. Advances in genetic and epigenetic profiling, proteomic expression data and metabolomics have generated an immense breadth of data, thereby highlighting the heterogeneity of breast cancer amongst individual patients and populations and providing an opportunity to identify actionable targets (1). Translating these insights into real-world applications for breast cancer, given its increasing incidence and prevalence, is dependent on identifying these molecular targets through economically viable and scalable means (2).

Despite extensive study of novel targeted approaches to treatment, triple negative breast cancer (TNBC) patient outcomes remain inferior when compared to other subtypes. In line with the concept of precision oncology, study of patients harbouring germline pathogenic variants in BRCA1 and BRCA2 has demonstrated tumour sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). This treatment approach has improved progression free survival (PFS) in the setting of advanced disease and overall survival in early-stage disease (3,4). PARP inhibitors (PARPis) exploit the inability of BRCA1- and BRCA2-mutated cancers to repair DNA double-stranded breaks (DSBs) through homologous recombination repair (HRR) by disrupting the involvement of PARP in single-strand break repair signalling (5,6). These single-stranded DNA breaks propagate through to S phase of the cell cycle at which point they are converted to DSBs. Cells functionally deficient in breast cancer gene (BRCA) are unable to mount endogenous repair mechanisms and apoptosis ensues due to mitotic catastrophe (Figure 1).

Figure 1 Mechanism of PARP inhibitor sensitivity in HRR-deficient breast cancer. PARP inhibition prevents both PARP auto-PARylation and recruitment of DNA SSB repair machinery, trapping PARP at the site of the SSB. SSBs propagate to synthesis phase of the cell cycle and collide with replication machinery, leading to replication fork stalling and generating DSBs. In HRR-proficient breast cancer, DSBs are repaired through this high-fidelity repair pathway, promoting cell survival. In HRR-deficient breast cancer, DSBs persist or are repaired via error-prone NHEJ, resulting in overwhelming genome instability and synthetic lethality. Permission was obtained from BioRender.com. SSB, single-stranded break; PARP, poly(ADP-ribose) polymerase; HRR, homologous recombination repair; DSBs, DNA double-stranded breaks; NHEJ, non-homologous end joining.

In the absence of a pathogenic germline BRCA mutation, standard first line therapy for metastatic TNBC remains cytotoxic chemotherapy, typically consisting of a platinum plus a taxane backbone, alongside immunotherapy for tumours expressing the immune checkpoint ligand programmed cell death ligand 1 (PD-L1) with a combined positive score ≥10. These regimens, while having improved patient outcomes (7), are marred with toxicity, have issues with access, and notably immunotherapy is not suitable for all patients. An attractive alternative to indefinite cytotoxic therapy is limited-course induction chemotherapy followed by maintenance treatment with targeted therapies, which incur fewer side effects and may confer a better quality of life. In the field of ovarian cancer therapeutics, PARPis have been enlisted as maintenance therapy following a response to platinum-based chemotherapy (8). This benefit may extend beyond patients with germline BRCA mutations, not only for ovarian cancer (9,10) but in TNBC as well. The S1416 trial has recently suggested a PFS benefit when the PARPi veliparib was combined with cisplatin [5.9 months, 95% confidence interval (CI): 4.3–7.8] compared to cisplatin alone (4.2 months, 95% CI: 2.3–5.0) in metastatic TNBC patients with ‘BRCA-like’ disease, defined by high genomic instability score, somatic BRCA mutation, BRCA promoter methylation, or other germline HRR mutation (11). Nevertheless, the efficacy of chemotherapy-free, PARPi-based, maintenance therapy in metastatic TNBC has yet to be established.

In the randomized phase II DORA trial, Tan et al., acknowledging the poor tolerability of indefinite cytotoxic chemotherapy, sought to evaluate the efficacy of the PARPi olaparib with or without the PD-L1 inhibitor durvalumab in patients who had derived clinical benefit from initial platinum therapy (12). In this multicentre international trial, 45 patients with locally advanced or metastatic triple negative or estrogen/progesterone receptor low (≤10% tumour cell expression) breast cancer with complete response (CR), partial response (PR), or stable disease after a minimum of three cycles of platinum-based chemotherapy were randomized to receive maintenance olaparib 300 mg twice daily or olaparib plus durvalumab 1,500 mg every 28 days. Of note, there was not a control arm without olaparib exposure. Maintenance therapy was continued until objective disease progression.

Median PFS from time of randomization after platinum-based induction was 4 months in the olaparib monotherapy group and 6.1 months in the combination olaparib and durvalumab group, both of which were significantly greater than the historical reference without maintenance therapy (12). This benefit appeared to be more pronounced amongst patients in both trial arms who had achieved CR or PR to platinum therapy when compared to those who had stable disease on a platinum-based regimen (5.4 versus 2.2 months in the olaparib arm and 7.6 versus 4.4 months in the combination arm), though this was not statistically significant in either treatment arm.

This trial is the first of its kind to utilize ongoing clinical response to front line platinum-based therapy as a trigger for transition to PARPi-based maintenance in TNBC. The study concept is in line with the phase II SAFIR-02 BREAST IMMUNO trial which employs a similar switch to more tolerable maintenance durvalumab following induction chemotherapy in metastatic breast cancer (13). While durvalumab maintenance therapy did not offer improved overall survival or PFS in the overall population, subgroup analysis demonstrated that in the TNBC cohort, durvalumab-treated patients had improved overall survival (21.2 months) when compared to those continued on cytotoxic chemotherapy (14.0 months). No difference in PFS between maintenance immunotherapy and chemotherapy was seen in this subset of patients, nor in the overall analysis with PFS in the durvalumab and chemotherapy arms of 2.7 and 4.6 months respectively. These were comparable to PFS reported in olaparib-treated patients included in the DORA trial.

In the absence of curative intent treatment in metastatic TNBC, therapeutic goals are to prolong survival with meaningful quality of life, in keeping with the principles of targeted maintenance therapy. While the DORA trial reports prolonged median PFS with PARPi-based maintenance therapy, it lacks survival data and patient-reported outcome measurements. Furthermore, PARPi-based maintenance therapy has a greater cost-per-treatment cycle than conventional chemotherapeutic protocols (14) as well as some toxicity, albeit less than with many chemotherapy regimens. As such, compelling evidence demonstrating improved overall survival or quality of life data becomes imperative to justify the cost-effectiveness of this approach in the context of TNBC.

Such patient-reported outcome measurements would be of heightened value in all persons, but particularly in elderly patients. The impact of extended cytotoxic chemotherapy on quality of life is often amplified in this cohort due to multimorbidity and associated end organ dysfunction, clinical frailty, and limited functional reserve to tolerate adverse events rendering more tolerable maintenance therapy particularly attractive in this group (15). Only 11% (5/45) of patients included in this study were over 65 and only one patient had an Eastern Cooperative Oncology Group (ECOG) score higher than one (12). Acknowledging that patients with TNBC are generally younger than those afflicted with hormone-receptor positive disease, greater representation of an elderly, functionally impaired cohort would be helpful to corroborate tolerability in this population that may not otherwise be suitable for indefinite intensive cytotoxic regimens.

Since the 2014 Food and Drug Administration (FDA) approval of olaparib as maintenance treatment in BRCA-mutated high-grade platinum sensitive epithelial ovarian cancer, it has become evident that the benefit of PARPi in ovarian cancer extends beyond BRCA mutational status to encompass HRR-mutated tumours and those with prior response to platinum therapy (10,16,17), but this has not yet been extended to breast cancer patients. The DORA trial builds from findings of recent studies that indicate that mechanisms of TNBC susceptibility to PARPi are not solely a result of mutation in BRCA or HRR signaling genes. Thirty-three of the 45 enrolled patients had no HRR mutations identified on initial tumour sampling. Furthermore, a robust response with a CR or PR to prior platinum regimen appeared to be more strongly associated with improved PFS in patients treated with olaparib monotherapy. Seven of eight patients with a CR or PR to platinum regimen achieved PFS of 6 months on olaparib while only one of eight had a known germline BRCA2 mutation. This may suggest that, as in the realm of ovarian cancer treatment, response to platinum chemotherapy can identify non-BRCA mutated patients that may benefit from extended PARPi maintenance therapy. A greater data pool is required to draw definitive conclusions and as such, these results should prompt further investigation to identify the characteristics of a broader cohort beyond TNBC patients harbouring germline BRCA mutation that may derive benefit from PARPi maintenance. In turn, this would avoid depriving these patients of a possible therapeutic opportunity due to stringent mutational assay-based eligibility criteria. A dynamic marker for sensitivity may be pragmatic and appropriate, similar to the work that is being done in estrogen receptor positive cancers using a KI67 decrease as a response criterion (18). It is also critical to ascertain whether alternative definitions of BRCAness, such as BRCA promoter methylation and high genomic instability scores, as had been defined in the S1416 trial, contribute to response in germline BRCA-wildtype patients to further identify persons who may benefit (11).

While this study serves as a brave inquiry into the feasibility of PARPi maintenance therapy in the setting of TNBC, the firm conclusions that can be drawn regarding the efficacy of such an approach are limited by the control selection, a small patient cohort, and prior immune checkpoint inhibitor (ICI) exposure. The DORA trial derived a historical PFS comparator of 2 months after platinum induction without maintenance therapy from KEYNOTE-355, citing a PFS of 5.6 months in the chemotherapy plus placebo arm of this trial (7). This PFS data reflects predominantly chemotherapy naïve patients who were treated with either a platinum- or taxane-based regimen, while all patients enrolled in DORA were platinum-pretreated. To mitigate the taxane-treated confounding patient group in this historical control, PFS of patients from the TNT trial with ongoing response to platinum chemotherapy at 3 months could be a more suitable alternative comparator (19). Slow patient recruitment further limits interpretation of this study’s findings, with only 45 patients enrolled after nearly 23 months, rendering both treatment arms statistically underpowered (12). In addition, given the non-comparative nature of the study, the relative impact of the addition of durvalumab to PARPi-based maintenance therapy cannot be defined. The amendment of study protocol that allowed prior ICI exposure further limits interpretation of durvalumab benefit particularly given that the number of patients previously treated with ICI and prior response to, or progression on, ICI is not described. Finally, as pharmacogenomics may also impact both response and toxicity, a large study with a diverse population is important to verify and broaden applicability of these results.

Though PARPis and platinum chemotherapy induce DNA damage through different mechanisms with a buildup of single-stranded breaks following inhibition of PARP and DNA crosslinking following platinum-based treatment, they share a common genotoxic outcome of DNA DSB induction (5,20). The shared mechanism of BRCA-mutated cancer sensitivity to PARPi and platinum chemotherapy is impairment in function of HRR to combat these DSBs. Acknowledging its limitations, the DORA trial should provoke further study of the following implications of these mechanistic similarities in the application of sequential treatment with platinum-regimens and PARPi-based maintenance therapy.

While PARPis are well established in the treatment of ovarian cancer following 6-month platinum treatment induction (10), the DORA trial considered a 63-day induction period as the minimum sufficient to classify disease as platinum-sensitive and to qualify these patients for PARPi maintenance. Optimization of platinum induction duration so as to minimize cumulative adverse effects of cytotoxic chemotherapy while maintaining survival benefit will be crucial.

Further, given the mechanistic similarities of PARPi and platinum cytotoxicity, it is of interest to explore whether, in the setting of metastatic TNBC, progression on olaparib maintenance would preclude clinical benefit from re-initiation of platinum-based therapy. Small retrospective analyses of patients with progression of epithelial ovarian cancer on PARPi suggest poor response to subsequent platinum therapy (21). Additionally, a small study of eight patients with metastatic TNBC and germline or somatic BRCA mutation who progressed on PARPi or platinum therapy found that on post-progression tumour sampling, half demonstrated somatic BRCA reversion mutations and those that were rechallenged with PARPi or platinum were resistant (22). Outcomes of platinum rechallenge following PARPi has yet to be investigated in large breast cancer cohorts and as such, post-progression data from the DORA olaparib arm would be of clinical interest.

Lastly, PARPi resistance in breast cancer develops through numerous mechanisms, often driven by BRCA reversion mutations, induction of cell proliferation pathways, and promotion of cellular drug efflux (23). The DORA trial collected both archival (pre-platinum) and fresh (post-platinum induction), PARPi naïve tumour samples. Comparative next generation sequencing of these samples with reacquired post-PARPi tissue will be of great interest to further elucidate the mutational landscape that promotes PARPi sensitivity and resistance. Similarly, we eagerly await the exploratory results of HRR gene methylation status through the DORA trial to examine the role of epigenetic alteration in PARPi resistance.

In summary, the DORA trial represents a provocative initial step in showcasing the clinical appeal and feasibility of a PARPi-based chemotherapy-free maintenance treatment for metastatic TNBC and should prompt further exploration of patient-reported quality of life outcomes in this setting. While interpretation of PFS data is limited by control selection and underpowered treatment arms, we applaud the investigators for this innovative trial as it lays the groundwork for further exploration of sequential platinum-PARPi treatment. Through further investigations of the line of questioning brought forward by the DORA trial, we believe that we may glean greater clarity regarding mechanisms of PARPi resistance in the setting of platinum pre-treated TNBC. This in turn will enable more appropriate selection of patients who may benefit from such an approach beyond those harbouring a germline BRCA mutation.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-44/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-44/coif). N.L. received grants to institution from Astra Zeneca, Exact Sciences, Gilead, Lilly, Pfizer, Roche; collaborated on educational events with Lilly, Gilead, Merck, Novartis, Roche, Seagen; and was on the Advisory Board of AstraZeneca, Lilly, Gilead, Merck, Knight, Novartis, Pfizer, Roche, Seagen, Tersera. K.A.G. received research grants from AZ, Pfizer, BMS, Roche; payments/honoraria from AstraZeneca, Lilly, Pfizer, Novartis, Gilead for lectures at meetings; participated in Canadian Advisory Boards related to BRCA testing in Canada, International Advisory Board and Data Safety Monitoring Board of a number of agents being developed by Astra Zeneca but not related to Olaparib, as well as Advisory Board and Data Safety Monitoring Board of AstraZeneca, Pfizer, Gilead, Lilly, Novartis, Merck, City of Hope, Ayala; and played leadership or fiduciary role in Canadian Breast Cancer Network, Rethink Breast Cancer. None of these activities have influenced this commentary except a familiarity and expertise in the area. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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