PARP Inhibitors In Ovarian Cancer Research Articles

Effect of MYC and PARP Inhibitors in Ovarian Cancer Using an In Vitro Model.

The 8q24 chromosomal region, which contains the MYC and PVT1 candidate oncogenes, is amplified in carcinomas. Both genes have been involved in the etiopathogenesis of ovarian cancer (OC). In this study, we used an in vitro OC model with a known 8q24 copy number increase and in silico tools to investigate the expression of MYC/PVT1 loci and copy number variation in OC. We also assessed the effects of rucaparib (a PARP inhibitor) in the presence or absence of 10058F4 (a MYC inhibitor) on the expression of MYC/linear PVT1/circular PVT1. Tissue culture, chromosome preparation, RNA extraction, RT-qPCR, FISH, and wound healing assays were employed. OncoDB, cBioportal, UALKAN, and ROC Plotter in silico tools were also utilized. Although PVT1 and MYC expression levels remained unaltered in OC, putative copy number alterations across all cancers showed a marked difference between the two genes, particularly in gain and amplification for MYC. PVT1 expression demonstrated prognostic value for the treatment of patients with serous and endometrioid OC. Both genes correlated with PARP10, FAM83H, and DEPTOR. The use of rucaparib in the presence or absence of the MYC inhibitor (10058F4) in vitro, led to a significant down-regulation in the expression of MYC, linear, and circular PVT1. Our data provide a novel insight into the potential interactions of MYC and PVT1 with other genes. Moreover, we identified a new PARP inhibition mechanism down-regulating MYC, as well as the linear and circular PVT1 transcripts. Future work should expand on clinical studies to better understand the prognostic role of PVT1 in OC.

Abstract 7135: Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer

Abstract Purpose: Among gynecological malignancies, ovarian cancer is the leading cause of mortality. Poly (ADP-ribose) polymerase inhibitors (PARPi) represent standard-of-care treatment for selected cases of advanced epithelial ovarian cancer. PARPi exhibit sensitivity in homologues recombination deficient (HRD) tumors, in which there are mutations in the Fanconi Anemia (FA)-BRCA pathway, while about 75% of ovarian cancer patients are homologues recombination proficient (HRP). TTFields are non-invasive electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Recent research showed that TTFields induce an HRD-like state (also known as BRCAness state) in various cancer types. The current study aims to investigate the impact of TTFields applied together with PARPi in ovarian cancer preclinical models. Methods: In vitro, A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with addition of PARPi (olaparib or niraparib, at various concentrations). Efficacy was measured by analyzing cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying cell count with colony formation. TTFields-treated cells were evaluated for the expression of FA-BRCA pathway proteins and for formation of γH2AX, a DNA damage marker, using Western blot and fluorescent microscopy, respectively. In vivo, ID8-fLuc (HRP) cells were inoculated intraperitoneally to 6-8-week-old C57BL/6 mice. Seven days post inoculation, mice were treated with sham-vehicle, TTFields, olaparib (50 mg/kg), or both over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation, and survival analysis was performed. Results: TTFields application resulted in reduced cell count, increased overall effect, and increased apoptosis in vitro. When TTFields were applied together with PARPi, a high and moderate synergistic interaction was shown respectively the BRCA wild-type A2780 cells and the platinum-resistant A2780cis cells. However, in the BRCA mutant OVCAR-3 cells the effect was additive. A downregulation of FA-BRCA protein expression was confirmed after TTFields treatment of the ovarian cells, with consequent DNA damage. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to the monotherapies and to control-treated mice. Conclusions: The data suggest potential advantages for TTFields concomitant with PARPi in ovarian cancer, even without underlying BRCA mutations - consistent with the BRCAness state induced by TTFields - and also suggests benefits in platinum-resistant ovarian cancer. Citation Format: Yani Berckmans, Hila Ene, Kerem Ben-Meir, Antonia Martinez-Conde, Roni Monin, Bieke Van den Ende, Sara Van Mechelen, Roni Frechtel-Gerzi, Hila Gabay, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Ignace Vergote, An Coosemans. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7135.

A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer

PurposeOvarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. MethodsThe SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays. ResultsSIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer. ConclusionsSIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.

Prior authorization for FDA-approved PARP inhibitors in ovarian cancer

ObjectivesPARP inhibitors (PARP-I) improve survival in ovarian cancer, especially in patients with germline or somatic BRCA mutations or other homologous recombination deficiency (HRD). With high efficacy and costs, insurers may enact barriers or facilitators to PARP-I. Our objective was to examine the prevalence of prior authorization for PARP-I in ovarian cancer. MethodsWe performed a retrospective cross-sectional study of patients with ovarian cancer prescribed a PARP-I within the University of Pennsylvania practices from December 2018 through May 2021. We assessed prevalence of prior authorization for PARP-I overall, by frontline or recurrent maintenance, and by genetic status. We then assessed approval and appeal rates and time to PARP-I start. ResultsOf 180 patients with a PARP-I prescription and information regarding prior authorization, 116 (64 %, 95 % CI 57–71) experienced prior authorization. Of patients in the frontline setting, 60 of 90 (67 %, 95 % CI 56–76) experienced prior authorization. Of patients prescribed PARP-I in recurrence, 55 of 85 (65 %, 95 % CI 54–74) experienced prior authorization. Having a germline or somatic genetic mutation was associated with higher risk of prior authorization (adjusted risk ratio 1.35, 95 %CI 1.09–1.67). 102 patients (89 %, 95 % CI 83–94) required one appeal, 8 required two appeals and 5 cases required 3 appeals. Five patients were denied. Mean time from PARP-I prescription to PARP-I start was 10 days longer for patients who experienced prior authorization. Conclusions64% of patients experienced prior authorization for PARP-I. Risk of prior authorization was increased for patients with BRCA, despite greater clinical benefit. Prior authorization contributes to delays in care, and reform is needed.

Clinical and molecular biomarkers predicting response to PARP inhibitors in ovarian cancer

Clinical and molecular biomarkers predicting response to PARP inhibitors in ovarian cancer

Comprehensive Review on PARP Inhibitors in Ovarian Cancer: A Breakthrough in Diagnostic and Therapeutic Approaches

Comprehensive Review on PARP Inhibitors in Ovarian Cancer: A Breakthrough in Diagnostic and Therapeutic Approaches

Efficacy and Safety of PARP Inhibitor Therapy in Advanced Ovarian Cancer: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

This study aims to evaluate the efficacy and safety of PARP inhibitor therapy in advanced ovarian cancer and identify the optimal treatment for the survival of patients. The diversity of PARP inhibitors makes clinicians confused about the optimal strategy and the most effective BRCAm mutation-based regimen for the survival of patients with advanced ovarian cancer. The objective of this study is to compare the effects of various PARP inhibitors alone or in combination with other agents in advanced ovarian cancer. PubMed, Embase, Cochrane Library, and Web of Science were searched for relevant studies on PARP inhibitors for ovarian cancer. Bayesian network meta-analysis was performed using Stata 15.0 and R 4.0.4. The primary outcome was the overall PFS, and the secondary outcomes included OS, AE3, DISAE, and TFST. Fifteen studies involving 5,788 participants were included. The Bayesian network metaanalysis results showed that olaparibANDAI was the most beneficial in prolonging overall PFS and non-BRCAm PFS, followed by niraparibANDAI. However, for BRCAm patients, olaparibTR might be the most effective, followed by niraparibANDAI. Olaparib was the most effective for the OS of BRCAm patients. AI, olaparibANDAI, and veliparibTR were more likely to induce grade 3 or higher adverse events. AI and olaparibANDAI were more likely to cause DISAE. PARP inhibitors are beneficial to the survival of patients with advanced ovarian cancer. The olaparibTR is the most effective for BRCAm patients, whereas olaparibANDAI and niraparibANDAI are preferable for non-BRCAm patients. Other: More high-quality studies are desired to investigate the efficacy and safety of PARP inhibitors in patients with other genetic performances.

A novel SIK2 inhibitor SIC-19 is synthetic lethal with PARP inhibitors in ovarian cancer (2298)

A novel SIK2 inhibitor SIC-19 is synthetic lethal with PARP inhibitors in ovarian cancer (2298)

Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer.

To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)-derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.

PARP inhibitors and overall survival in ovarian cancer, reevaluation advised in all settings.

PARP inhibitors in ovarian cancer have been a breakthrough therapy of the past decade, driven by positive trial results, and supported by an original pharmacological rationale. However, with mature data, detrimental survival results led to the withdrawals, in 2022, of all approved PARP inhibitors in the most advanced settings' indication (as monotherapy in third or subsequent lines) by the US Food and Drug Administration (FDA). Two other indications, as maintenance after relapse, were also restricted. In this work, based on pooled meta-analysis in each setting, we question a unique situation in oncology: a survivalbenefit is seen in front-line settings, with, at the same time, a survivaldecrement in later lines. Either this original feature is explained by the unique biological action of PARP inhibitors-through synthetic lethality-in patients with ovarian cancer and homologous repair deficiency. Another explanation may be trial design: decrement in later lines could partly explain why beneficial results were seen in early settings, simply by avoiding late exposure to PARP inhibitors in the experimental arm in those trials. High crossover rates seen in some trials further support this alternate hypothesis. We contend our analysis and recent survival results of PARP inhibitors warrant a whole reassessment of the place of these compounds in the landscape of ovarian cancer treatments.

Abstract 6182: Tumor treating fields (TTFields) concomitant with PARP inhibitors or carboplatin for treatment of ovarian cancer cell lines

Abstract Purpose/Objectives: Ovarian cancer continues to be the leading cause of death among gynecological malignancies. Platinum-based chemotherapy is recommended after surgery for most patients with ovarian cancer; and PARP inhibitors (PARPi) are suggested as maintenance therapy. Both therapies induce DNA damage that require the proper activity of the Fanconi Anemia (FA)- BRCA pathway for its resolution, and hence are most beneficial in cancers with a BRCA mutation. However, 75% of patients with ovarian cancer do not harbor BRCA mutations, and thus may experience limited benefit from these treatments. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cancer cell death. Recently, TTFields have been shown to induce a state of BRCAness in various cancer types, and to be effective in ovarian cancer pre-clinical models. The objective of the current study was to examine the effect of TTFields concomitant with carboplatin or PARPi on ovarian cancer cell lines. Materials/Methods: A2780 (BRCA wild type) and OVCAR3 (BRCA mutated) ovarian carcinoma cells were treated with TTFields (72 h, 1 V/cm RMS, 200 kHz), alone or with concomitant application of carboplatin or the PARP inhibitors olaparib or niraparib. Efficacy was examined via measurements of cell count, colony formation, and induction of apoptosis. The overall effect was calculated by multiplying cell count with colony formation. Results: Application of TTFields to A2780 or OVCAR3 cells resulted in reduced cell count, increased overall effect, and elevated apoptosis. Carboplatin, olaparib, and niraparib each displayed dose dependent effects in both cell lines, with higher sensitivity demonstrated in the BRCA mutated cells. Concomitant application of TTFields with any of these drugs displayed a synergistic interaction in the BRCA wild type A2780 cells and an additive effect in the BRCA mutant OVCAR-3 cells. Conclusions: The data suggest potential benefits for TTFields concomitant with platinum-based chemotherapy and PARPi in ovarian cancer, even in the absence of background BRCA mutations, in accordance with the BRCAness state induced by TTFields. As such, TTFields may enhance the efficacy of treatment for ovarian cancer in both the adjuvant and maintenance settings. Citation Format: Antonia Martinez-Conde, Hila Ene, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Tumor treating fields (TTFields) concomitant with PARP inhibitors or carboplatin for treatment of ovarian cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6182.

Abstract 5694: Adaptive treatment scheduling of PARP inhibitors in ovarian cancer: Using mathematical modeling to assess clinical feasibility and estimate potential benefits

Abstract PARP inhibitors (PARPis) are revolutionizing the treatment of ovarian cancer. Yet for many patients these improvements come at the cost of physical and financial toxicity and responses are typically temporary due to emerging drug resistance. A growing body of pre-clinical and clinical work suggests that when cure is unlikely, it is possible to delay progression and reduce drug use through patient-specific drug scheduling. So-called 'adaptive therapy' dynamically adjusts treatment to preserve drug-sensitive cells which interfere with resistant cells through competition. In a prior study, we developed a mathematical model to describe the treatment response of ovarian cancer cells to the PARPi olaparib in vitro, and we proposed a candidate adaptive PARPi algorithm. Here, we extend our model to capture the dynamics in patients and use it to study the feasibility and potential benefit of adaptive PARPi administration in practice. Our prior model posited that treatment induces cell cycle arrest that moves cells from the proliferating subset of the population to an arrested compartment. The model predicted that while there is scope for treatment reductions, these need to be carefully timed and prolonged treatment breaks should be avoided. Based on these results we proposed an adaptive treatment algorithm in which the olaparib dose is switched between high and low doses, depending on the tumor’s growth rate. To test the translational potential of this strategy, we retrospectively collected data from 53 ovarian cancer patients who received olaparib at the H Lee Moffitt Cancer Center between 2014 and 2021. Using serum CA-125 as a proxy for tumor burden, we first examined whether our mathematical model could capture the patients’ longitudinal dynamics. While the response of some patients was consistent with what we had observed in vitro, in others there was evidence of the emergence of a distinct drug-resistant population, and we extended our mathematical model to account for this. After calibrating and validating the model with the patient data, we tested whether these patients would have benefited from adaptive PARPi treatment. Our simulations suggest that our proposed algorithm is feasible and provides a means for reducing treatment in a patient-specific manner. In addition, in a subset of patients we predict that adaptive therapy could delay progression. Overall, this work corroborates the potential for adaptive PARPi therapy and helps to identify outstanding challenges on the way to clinical translation. Citation Format: Maximilian A. Strobl, Alexandra L. Martin, Christopher Gallagher, Mehdi Damaghi, Mark Robertson-Tessi, Robert Gatenby, Robert M. Wenham, Philip K. Maini, Alexander R. Anderson. Adaptive treatment scheduling of PARP inhibitors in ovarian cancer: Using mathematical modeling to assess clinical feasibility and estimate potential benefits. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5694.

24 The PARP-1-DDX21-ribosome biogenesis axis is an alternative pathway targeted by PARP inhibitors in ovarian cancer

24 The PARP-1-DDX21-ribosome biogenesis axis is an alternative pathway targeted by PARP inhibitors in ovarian cancer

570P Hypomethylating agents synergistically combine with PARP inhibitors in ovarian cancer

Poly (ADP-Ribose) polymerase inhibitors (PARPi’s) are currently used for first and second line maintenance therapy of ovarian cancer (OC) in patients whose tumors harbor defects in homologous recombination. Unfortunately, the rapid emergence of resistance leads to a short duration of response, and thus preventing PARPi resistance and extending the spectrum of patients who would benefit from PARP inhibition are urgent needs. While multiple drug classes have demonstrated synergy when combined with PARPi’s preclinically, head-to-head comparisons which would facilitate clinical prioritization of the most promising combinations are missing.

Development of an interactive precision medicine dashboard to aid in completion of germline and homologous recombination deficiency (HRD) tumor testing for newly diagnosed ovarian cancer patients to improve the use of PARP inhibitor frontline maintenance (583)

Objectives: New approvals for upfront maintenance therapy with PARP inhibitors in ovarian cancer necessitate efficient germline genetic testing and Homologous Recombination Deficiency (HRD) testing within several months of diagnosis to aid in consideration of PARP inhibitors for frontline maintenance treatment. Despite being recommended for all newly diagnosed epithelial ovarian cancer cases, national rates of germline genetic testing are approximately 30%1. The testing process can be overly manual, prone to delays and missed opportunities for timely PARP initiation. Completion of testing often involves multiple steps, including the use of different testing companies, without a clear way to track patients’ progress in the process. A previous trial aimed at applying novel healthcare innovation techniques to this problem was conducted to identify the optimal approach to improve germline and somatic tumor testing rates in newly diagnosed ovarian cancer patients2. Based on the results of this trial, we developed and implemented an interactive precision medicine dashboard for tracking germline and HRD testing pathway completion tracking and PARP inhibitor prescribing. Methods: After previously conducting four pilots trialing various behavioral economic interventions2, it was determined that the development of an interactive dashboard would be the most effective solution to improve genetic testing completion and timely PARP delivery. We first implemented automation and choice architecture utilizing the EMR to surface missing clinical information while removing the provider’s mental burden of the work required to complete necessary testing. We then developed the “PreAct: Precision Medicine Activated” Dashboard to filter patients by priority status, clear identification of patient data, interactive notes, and data report- ing3. After the initial implementation of the dashboard, delays were noted in time to HRD testing for germline negative patients; thus, reflex HRD testing was initiated in an effort to further streamline the process. Results: After implementation, our genetic testing rates increased from 65% to 94%. We improved our time to genetic testing from a range of 100-150 days in 2019 to 20 days. Potential trends in racial disparities were identified, with 70% of current patients who missed testing being identified as Black. Given the utility of PreAct, this dashboard is being expanded to other disease sites, including abnormal somatic testing in colon/uterine cancer and metastatic breast cancer. Conclusions: The development of an interactive dashboard improves rates of genetic testing for ovarian cancer and aids in the facilitation of timely PARP initiation when applicable. The precision medicine dashboard automates work to reduce the cognitive burden for clinicians. An innovative “concierge approach” to assist patients who have missed testing could be used to “rescue” patients that have fallen off the pathway, as we have previously tested and demonstrated this method to be effective in moving patients forward in germline testing. Potential racial disparities need further exploration to ensure equitable and applicable solutions to all patients. Objectives: New approvals for upfront maintenance therapy with PARP inhibitors in ovarian cancer necessitate efficient germline genetic testing and Homologous Recombination Deficiency (HRD) testing within several months of diagnosis to aid in consideration of PARP inhibitors for frontline maintenance treatment. Despite being recommended for all newly diagnosed epithelial ovarian cancer cases, national rates of germline genetic testing are approximately 30%1. The testing process can be overly manual, prone to delays and missed opportunities for timely PARP initiation. Completion of testing often involves multiple steps, including the use of different testing companies, without a clear way to track patients’ progress in the process. A previous trial aimed at applying novel healthcare innovation techniques to this problem was conducted to identify the optimal approach to improve germline and somatic tumor testing rates in newly diagnosed ovarian cancer patients2. Based on the results of this trial, we developed and implemented an interactive precision medicine dashboard for tracking germline and HRD testing pathway completion tracking and PARP inhibitor prescribing. Methods: After previously conducting four pilots trialing various behavioral economic interventions2, it was determined that the development of an interactive dashboard would be the most effective solution to improve genetic testing completion and timely PARP delivery. We first implemented automation and choice architecture utilizing the EMR to surface missing clinical information while removing the provider’s mental burden of the work required to complete necessary testing. We then developed the “PreAct: Precision Medicine Activated” Dashboard to filter patients by priority status, clear identification of patient data, interactive notes, and data report- ing3. After the initial implementation of the dashboard, delays were noted in time to HRD testing for germline negative patients; thus, reflex HRD testing was initiated in an effort to further streamline the process. Results: After implementation, our genetic testing rates increased from 65% to 94%. We improved our time to genetic testing from a range of 100-150 days in 2019 to 20 days. Potential trends in racial disparities were identified, with 70% of current patients who missed testing being identified as Black. Given the utility of PreAct, this dashboard is being expanded to other disease sites, including abnormal somatic testing in colon/uterine cancer and metastatic breast cancer. Conclusions: The development of an interactive dashboard improves rates of genetic testing for ovarian cancer and aids in the facilitation of timely PARP initiation when applicable. The precision medicine dashboard automates work to reduce the cognitive burden for clinicians. An innovative “concierge approach” to assist patients who have missed testing could be used to “rescue” patients that have fallen off the pathway, as we have previously tested and demonstrated this method to be effective in moving patients forward in germline testing. Potential racial disparities need further exploration to ensure equitable and applicable solutions to all patients.

Streamline of the gene line: Implementation of reflex homologous recombination deficiency (HRD) tumor testing in newly diagnosed ovarian cancer patients (593)

Objectives: New approvals for frontline maintenance therapy with PARP inhibitors in ovarian cancer necessitate efficient germline genetic testing and Homologous Recombination Deficiency (HRD) testing within months of diagnosis to aid in consideration of PARP inhibitors for frontline maintenance. Based on the results of a previous trial, our institution recently developed and implemented an interactive dashboard tracking germline and HRD testing pathway completion and PARP inhibitor prescribing. Initial dashboard output highlighted persistent delays and misses in time-to-completion of HRD testing for germline negative patients; thus, reflex HRD testing was initiated to further streamline the process. The current study sought to investigate the feasibility of the implementation of reflex HRD testing and its potential effect on testing completion rates. Methods: Patients with newly diagnosed epithelial ovarian cancer who were negative for a germline BRCA mutation were extracted from the previously described “PreAct: Precision Medicine Activated” Dashboard over six months before and after implementing HRD reflex testing (September 1, 2020, to March 1, 2021, and March 1, 2021, to September 1, 2021). HRD reflex testing was ordered and performed through Myriad MyChoice® with a single test request form (TRF), streamlining the previous process of multiple order forms at different timepoints. Prior to implementing HRD reflex testing, some providers at our institution were using Caris® molecular testing (LOH status) alone to determine eligibility for PARP without additional HRD testing. HRD reflex testing was implemented to increase testing compliance and institutional process alignment. Patients with Caris® results but without HRD results were considered incompletely evaluated for this analysis. Patient demographics, timings of genetic consult, testing, and PARP initiation were collected. Descriptive statistics were performed. Results: During the pre-reflex testing period (Pre-R), 24 patients met the inclusion criteria, while 18 patients met the criteria during the post-reflex testing period (Post-R). Five Pre-R patients successfully completed the germline-HRD testing pathway (5/24, 20.8%), while nine Post-R patients completed the pathway (9/18, 50%). Two additional Post-R patients had reflex testing not yet resulted at the time of submission. Of patients who completed the pathway successfully, Pre-R patients had a median time from germline to HRD testing of 53 days, while the Post-R median time-to-completion was 21 days (p<.01). Ten (41.6%) Pre-R patients had no additional testing following negative germline result, compared to four Post-R patients (22.2%). Of Post-R patients who did not complete the testing pathway following germline testing, 2/4 had germline testing ordered the month that reflex testing was initiated. Prior to implementing HRD reflex, nine patients had Caris and germline but no HRD testing (37.5%). Three (16.6%) Post-R patients had Caris with no HRD testing, although one was ordered on the month of implementation and one was documented as reflex ordered through MyChoice® though not resulted. Conclusions: Institutional adoption of HRD reflex testing following negative germline testing in newly diagnosed ovarian cancer patients is feasible. Reflex testing has the potential to increase testing rates and decrease time to completion with a decrease in the cognitive burden on providers, allowing for targeted application of timely PARP inhibitors in the frontline maintenance setting. Objectives: New approvals for frontline maintenance therapy with PARP inhibitors in ovarian cancer necessitate efficient germline genetic testing and Homologous Recombination Deficiency (HRD) testing within months of diagnosis to aid in consideration of PARP inhibitors for frontline maintenance. Based on the results of a previous trial, our institution recently developed and implemented an interactive dashboard tracking germline and HRD testing pathway completion and PARP inhibitor prescribing. Initial dashboard output highlighted persistent delays and misses in time-to-completion of HRD testing for germline negative patients; thus, reflex HRD testing was initiated to further streamline the process. The current study sought to investigate the feasibility of the implementation of reflex HRD testing and its potential effect on testing completion rates. Methods: Patients with newly diagnosed epithelial ovarian cancer who were negative for a germline BRCA mutation were extracted from the previously described “PreAct: Precision Medicine Activated” Dashboard over six months before and after implementing HRD reflex testing (September 1, 2020, to March 1, 2021, and March 1, 2021, to September 1, 2021). HRD reflex testing was ordered and performed through Myriad MyChoice® with a single test request form (TRF), streamlining the previous process of multiple order forms at different timepoints. Prior to implementing HRD reflex testing, some providers at our institution were using Caris® molecular testing (LOH status) alone to determine eligibility for PARP without additional HRD testing. HRD reflex testing was implemented to increase testing compliance and institutional process alignment. Patients with Caris® results but without HRD results were considered incompletely evaluated for this analysis. Patient demographics, timings of genetic consult, testing, and PARP initiation were collected. Descriptive statistics were performed. Results: During the pre-reflex testing period (Pre-R), 24 patients met the inclusion criteria, while 18 patients met the criteria during the post-reflex testing period (Post-R). Five Pre-R patients successfully completed the germline-HRD testing pathway (5/24, 20.8%), while nine Post-R patients completed the pathway (9/18, 50%). Two additional Post-R patients had reflex testing not yet resulted at the time of submission. Of patients who completed the pathway successfully, Pre-R patients had a median time from germline to HRD testing of 53 days, while the Post-R median time-to-completion was 21 days (p<.01). Ten (41.6%) Pre-R patients had no additional testing following negative germline result, compared to four Post-R patients (22.2%). Of Post-R patients who did not complete the testing pathway following germline testing, 2/4 had germline testing ordered the month that reflex testing was initiated. Prior to implementing HRD reflex, nine patients had Caris and germline but no HRD testing (37.5%). Three (16.6%) Post-R patients had Caris with no HRD testing, although one was ordered on the month of implementation and one was documented as reflex ordered through MyChoice® though not resulted. Conclusions: Institutional adoption of HRD reflex testing following negative germline testing in newly diagnosed ovarian cancer patients is feasible. Reflex testing has the potential to increase testing rates and decrease time to completion with a decrease in the cognitive burden on providers, allowing for targeted application of timely PARP inhibitors in the frontline maintenance setting.

SY23-3 Clinical development of PARP inhibitors in ovarian cancer

Initial clinical development of PARP inhibitor (PARPi) started for ovarian patients with germline BRCA mutation (gBRCAm) based on the mechanistic assumptions. The first large phase 3 trial, SOLO2, focused on the patient with platinum-sensitive recurrent ovarian cancer known to have gBRCAm. On the other hand, the NOVA trial tested the innovative study design. The investigators challenged to include patients with not only gBRCAm but also with non-gBRCAm, which included HRD+ (tBRCAm only and BRCAwt) and HRD-negative population.

Abstract 3249: Targeting polyploid giant cancer cells to overcome resistance to PARP inhibitors in ovarian cancer

Abstract PARP inhibitors (PARPi) offer major clinical benefit for patients with ovarian or other cancers, especially those with deficiencies in the homologous recombination DNA repair pathway. However, most patients with advanced cancer eventually acquire resistance to PARPi, and the mechanisms by which tumors escape PARPi therapy are still not fully understood. Here, we report that treatment with the PARPi olaparib induces the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines (Hey, SKOV3, MCF-7), three human high-grade serous cancer (HGSC)-derived organoids, and HGSC patient-derived xenografts. Live-cell fluorescence time-lapse tracking of ovarian cancer cells labeled with FUCCI (fluorescent ubiquitination cell-cycle indicator) or histone H2B-mCherry/α-tubulin-EGFP revealed that PGCCs primarily developed from the endoreplication of diploid cancer cells after exposure to sublethal concentrations of olaparib. PGCCs exhibited markers of senescent cells; however, they were able to escape senescence to generate mitotically competent daughter cells via budding, multipolar mitosis, and acytokinetic mitosis following olaparib withdrawal. PGCCs and derived daughter cells conferred resistance to olaparib-induced cytotoxicity, which could be blocked by the anti-progesterone drug mifepristone. Whole transcriptome analysis by RNA sequencing of ovarian cancer cell lines and ovarian cancer-derived organoids showed activation of a senescence-associated secretory phenotype with upregulated cytokines and chemokines and downregulation of MYC signaling in PGCCs. Mifepristone/olaparib combination therapy significantly mitigated tumor growth in patient-derived xenograft models with acquired resistance to olaparib. Thus, targeting of PGCCs may represent a promising approach to overcome PARPi resistance in recurrent ovarian cancer. Citation Format: Xudong Zhang, Jun Yao, Xiaoran Li, Na Niu, Yan Liu, Anil K. Sood, Jinsong Liu. Targeting polyploid giant cancer cells to overcome resistance to PARP inhibitors in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3249.

Prior authorizations for PARP inhibitors in ovarian cancer.

5549 Background: PARP inhibitors improve survival in ovarian cancer, especially in patients with BRCA 1/2 mutations or homologous recombination deficiency (HRD). However, these FDA-approved drugs cost $100,000 annually on average, and concerns have been raised about insurance barriers like prior authorization to such medications. Our objective was to examine the prevalence of prior authorization for PARP inhibitors in ovarian cancer overall, by frontline or recurrent maintenance, and by genetic status. Methods: We performed a retrospective cross-sectional study of ovarian cancer patients prescribed a PARP inhibitor within the University of Pennsylvania oncology practices from May 2020-2021. Using electronic medical records, we assessed the prevalence of prior authorization for PARP inhibitors overall, by frontline or recurrent maintenance, and by BRCA or HRD status. We then assessed the associated approval and appeal rates. Results: We identified 110 patients with ovarian cancer who were prescribed a PARP inhibitor. Of these, 67% (95%CI 57-75) experienced prior authorization for their PARP inhibitor. In contrast, 31 (95%CI 23-40) experienced prior authorization for other components of their gynecologic oncology care. Of patients in the frontline setting, 74 (95%CI 58-86) experienced prior authorization for FDA-approved PARP maintenance. Of patients prescribed PARP maintenance after recurrence, 58 (95%CI 45-71) experienced prior authorization. Of patients with germline BRCA, 70% (95%CI 47-85) experienced prior authorization for PARP inhibitors. Of patients with germline or somatic BRCA or HRD+, 76% (95%CI 61-87) experienced prior authorization. 95% (95%CI 86-94) of prior authorizations for PARP inhibitors were approved on their 1st appeal, and 99% (95%CI 95-100) were approved by the 2nd appeal. Conclusions: Two-thirds of patients of ovarian cancer patients who were prescribed PARP inhibitor experienced prior authorization, including equally high rates among women with germline or somatic BRCA mutations, as well as with HRD-deficient tumors. Given the nearly 100% approval after prior authorization, improvements in insurance processes are needed to streamline PARP inhibitor access in ovarian cancer.

Real-world use, tolerability, and dose modifications of PARP inhibitors in ovarian cancer.

5552 Background: Tolerability is a key consideration when selecting a PARP inhibitor (PARPi) for ovarian cancer (OC). Here we expand on earlier work (Arend et al 2021) to further characterize real-world tolerability and dose modifications in US patients (pts) with OC receiving PARPi therapy. Methods: A retrospective cohort of OC pts starting olaparib (ola), niraparib (nir) or rucaparib (ruc) between Jan 2017 and Dec 2020 was identified from MarketScan® Commercial/Medicare Supplemental databases, increasing the period covered and number of pts included vs our previous analysis. Pts were followed up from first PARPi prescription (index) for ≥30 days until end of study period, disenrollment or death; baseline was 6 months pre-index. Clinical events of interest (CEIs; acute myeloid leukemia/myelodysplastic syndromes, anemia, leukopenia/neutropenia, thrombocytopenia, acute kidney injury, arthralgia, constipation, diarrhea, nausea, vomiting, dermatitis/rash/photosensitivity, fatigue, hypertension, infection, insomnia, pneumonitis, transaminitis) were identified via ICD-9/10 codes. Multivariable Cox regression compared the likelihood of CEIs, dose modifications and hospitalizations between PARPis, adjusting for baseline CEI, Charlson Comorbidity Index score, prior bevacizumab and cancer-related surgery. Persistence was defined as no PARPi treatment gaps of &gt;90 days in pts with ≥6 months’ continuous enrollment. Results: Overall, 637, 538 and 227 pts received ola, nir and ruc, respectively (median [IQR] follow-up 10.5 [13.4] months). Baseline characteristics were similar across groups. The proportion of pts initiating PARPi at the highest indicated dose was 89.2%, 57.6% and 89.9% for ola, nir and ruc, respectively; 22.6%, 34.8% and 28.6%, respectively, required dose decreases. The likelihood of experiencing CEIs varied across the PARPis after adjusting for a priori confounders as shown in the table. Persistence with index PARPi was higher with ola (83.4%) vs nir (73.3%; P&lt;0.001) and similar vs ruc (80.2%; P&gt;0.05). Among all pts, mean time to non-persistence was shorter with nir vs ola and ruc (6.4 vs 7.9 and 7.6 months, respectively; both P&lt;0.05). CEIs by PARPi dose and calendar year will also be presented. Conclusions: This is the largest real-world comparison of PARPi use in OC pts reported to date. It supports differences between PARPis in persistence with therapy and risk of experiencing a CEI, even after adjusting for confounders. [Table: see text]