Poly(Adenosine Diphosphate Ribose) Polymerase (PARP) Inhibitors in the Treatment of Advanced Ovarian Cancer: A Narrative Review.

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors have appeared as a revolutionary approach to treating advanced ovarian cancer, particularly in patients with breast cancer (BRCA) mutations and homologous recombination deficiency (HRD). This narrative review explores PARP inhibitors' clinical efficiency, safety, and changing role in this context. PARP inhibitors, such as olaparib, niraparib, or rucaparib, provide considerable benefits regarding progression-free survival expansion and overall outcomes improvement in first-line maintenance and recurrent settings. The underlying mechanisms, patient selection criteria, and resistance patterns are discussed, alongside insights into combination therapies to overcome resistance and enhance therapeutic efficacy. Ongoing clinical trials and future potential for personalized therapy approaches using PARP inhibitors for advanced ovarian cancer are also highlighted. However, despite these drugs' phenomenal ability to revolutionize treatment protocols for such cancer types, several challenges remain: toxicity management, cost, and development of resistance will require more research to optimize their use or broaden patient populations who can benefit from them.

Efficacy and safety of PARP inhibitor maintenance therapy for ovarian cancer: a meta-analysis and trial sequential analysis of randomized controlled trials.

Background: The landscape of poly (ADP-ribose) polymerase (PARP) inhibitor treatment for ovarian cancer (OC) is continually evolving. This research aimed to evaluate the efficacy and safety of PARP inhibitors compared to placebo as a maintenance therapy for OC patients. Methods: We conducted a search of PubMed, Embase, Web of Science, and the Cochrane Library databases for randomized controlled trials (RCTs) involving the use of PARP inhibitors as maintenance therapy in OC patients, up to 16 June 2024. Data regarding progression-free survival (PFS), overall survival (OS), chemotherapy-free interval (CFI), time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), and treatment-emergent adverse events (TEAEs) were aggregated. Pooled hazard ratio (HR) and their corresponding 95% confidence intervals (CI) were calculated for PFS, OS, CFI, TFST, and TSST. Additionally, the relative risk (RR) and 95% CI for TEAEs were determined. Results: This meta-analysis encompassed 20 RCTs involving 7,832 participants. The overall analysis demonstrated that maintenance therapy with PARP inhibitors led to significant improvements in PFS (HR: 0.398, 95% CI = 0.339-0.467, 95% PI = 0.219-0.724), OS (HR: 0.677, 95% CI = 0.582-0.788, 95% PI = 0.546-0.839), CFI (HR: 0.417, 95% CI = 0.368-0.472, 95% PI = 0.265-0.627), TFST (HR: 0.441, 95% CI = 0.391-0.498, 95% PI = 0.308-0.632), and TSST (HR: 0.574, 95% CI = 0.507-0.649, 95% PI = 0.488-0.674) compared with placebo. Subgroup analyses further indicated that PARP inhibitor maintenance treatment significantly improved PFS, regardless of homologous recombination status (all p < 0.05). However, the risks of any grade (RR = 1.046, 95% CI = 1.032-1.059, 95% PI = 1.028-1.055) and grade ≥3 TEAEs (RR = 2.931, 95% CI = 2.641-3.253, 95% PI = 2.128-3.792) were increased by PARP inhibitor maintenance therapy compared to placebo. Conclusion: Our research elucidated the benefits of maintenance therapy with PARP inhibitors in patients with OC, showing improvements in PFS, OS, CFI, TFST, and TSST. Vigilance regarding TEAEs is paramount for clinicians implementing PARP inhibitor maintenance therapy in clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024560286.

Development and Characterization of Olaparib-Loaded Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Pharmaceutical Applications.

This study aims to enhance the solubility of Olaparib, classified as biopharmaceutical classification system (BCS) class IV due to its low solubility and bioavailability using a solid self-nanoemulsifying drug delivery system (S-SNEDDS). For this purpose, SNEDDS formulations were created using Capmul MCM as the oil, Tween 80 as the surfactant, and PEG 400 as the co-surfactant. The SNEDDS formulation containing olaparib (OLS-352), selected as the optimal formulation, showed a mean droplet size of 87.0 ± 0.4 nm and drug content of 5.53 ± 0.09%. OLS-352 also demonstrated anticancer activity against commonly studied ovarian (SK-OV-3) and breast (MCF-7) cancer cell lines. Aerosil® 200 and polyvinylpyrrolidone (PVP) K30 were selected as solid carriers, and S-SNEDDS formulations were prepared using the spray drying method. The drug concentration in S-SNEDDS showed no significant changes (98.4 ± 0.30%, 25℃) with temperature fluctuations during the 4-week period, demonstrating improved storage stability compared to liquid SNEDDS (L-SNEDDS). Dissolution tests under simulated gastric and intestinal conditions revealed enhanced drug release profiles compared to those of the raw drug. Additionally, the S-SNEDDS formulation showed a fourfold greater absorption in the Caco-2 assay than the raw drug, suggesting that S-SNEDDS could improve the oral bioavailability of poorly soluble drugs like olaparib, thus enhancing therapeutic outcomes. Furthermore, this study holds significance in crafting a potent and cost-effective pharmaceutical formulation tailored for the oral delivery of poorly soluble drugs.

Identification of BBC3 as a novel indicator for predicting prostate cancer development and olaparib resistance.

Prostate cancer (PCa) is a commonly occurring malignancy in elderly men. Olaparib, a poly ADP-ribose polymerase inhibitor, is utilized in PCa treatment. However, patients often develop resistance to olaparib after a period of treatment. Genetic alterations may play a significant role in this resistance, but the specific genes involved remain unclear. This study collected RNA-sequence data from the Gene Expression Omnibus database on both olaparib-sensitive and -resistant PCa cells to identify genes crucial for resistance. Subsequently, the enriched pathways of these genes were analyzed, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The effect of these hub genes on PCa occurrence, progression, and prognosis was assessed using data from The Cancer Genome Atlas and Chinese Prostate Cancer Genome and Epigenome Atlas databases. Finally, this study validated our findings in clinical PCa samples and cells. From the GSE189186 dataset, 50 upregulated genes and 2 downregulated genes were identified in olaparib-resistant C4-2B and LNCaP cells. Utilizing the PPI network, eight upregulated genes (BBC3, TP53I3, FDXR, DDB2, CDKN1A, GADD45A, ZMAT3, and SESN1) were identified as hub genes for olaparib-resistant PCa cells. Furthermore, some of these genes were central to PCa occurrence, with BBC3 also influencing progression and prognosis. Importantly, BBC3 expression was upregulated in clinical PCa samples and affected PCa cells sensitive to olaparib, suggesting its potential as a predictive marker for PCa development and olaparib resistance.

Melatonin increases Olaparib sensitivity and suppresses cancer-associated fibroblast infiltration via suppressing the LAMB3-CXCL2 axis in TNBC.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype, characterized with high aggressiveness and a high recurrence rate. Olaparib is the first US Food and Drug Administration-approved poly(ADP ribose) polymerase (PARP) inhibitor (PARPi) to treat breast cancer patients with a germline BRCA1 or BRCA2 mutation. However, resistance to Olaparib treatment restricts the therapeutic effects, and thus novel therapeutics are urgently required. In the present study, we identified that the combination of melatonin and Olaparib synergistically enhanced the sensitivity of TNBC cells. Moreover, melatonin exerted promising antitumor activities in Olaparib-resistant cells, implying the potential for its clinical application. An RNA-sequencing analysis revealed that melatonin treatment downregulated laminin subunit beta 3 (LAMB3) expression. Genetic ablation of LAMB3 significantly increased Olaparib sensitivity, and subsequently suppressed proliferation, epithelial-to-mesenchymal transition (EMT)-related gene expressions, and aggressiveness of breast cancer cells. Accordingly, LAMB3 expression was positively correlated with C-X-C motif chemokine ligand 2 (CXCL2), and they collaboratively promoted cancer-associated fibroblast (CAF) infiltration. An in vivo study demonstrated that combined treatment with melatonin and Olaparib showed enhanced inhibitory efficacy against tumor growth, LAMB3 expression, CXCL2 levels, and CAF infiltration compared to single treatment groups, and combined treatment with melatonin and Olaparib significantly ameliorated the immunosuppressive tumor microenvironment. These findings illustrate a promising therapeutic strategy using melatonin to overcome Olaparib resistance and activate antitumor immunity via attenuating the LAMB3-CXCL2 axis in breast cancer patients.

Prostate Cancer Therapy Cardiotoxicity Map (PROXMAP) for Advanced Disease States: A Systematic Review and Network Meta-analysis with Bayesian Modeling of Treatment Histories.

BACKGROUND AND OBJECTIVE: Recommendations of first-line therapies for metastatic hormone-sensitive (mHSPC), nonmetastatic castrate-resistant (M0CRPC), and metastatic castrate-resistant (mCRPC) prostate cancer do not account for cardiotoxicity due to a lack of clear prior evidence. This manuscript assesses cardiotoxicity of these therapies. METHODS: We searched Ovid Medline, Elsevier Embase, and the Cochrane Library for randomized clinical trials (RCTs) from database inception to January 14, 2024. Network meta-analyses of first-line mHSPC, M0CRPC, and mCRPC therapies were constructed for the five cardiotoxicity metrics defined by the International Cardio-Oncology Society: heart failure, myocarditis, vascular toxicity, hypertension, and arrhythmias. Additional Bayesian network meta-analyses also accounted for prior treatment history. KEY FINDINGS AND LIMITATIONS: Thirteen RCTs (16 292 patients) were included. For mHSPC, androgen deprivation therapy (ADT) plus docetaxel (DTX) plus abiraterone acetate (AA) with prednisone (P) demonstrated a significant increase in hypertension and arrhythmias versus ADT + DTX (risk ratio [RR] 2.85, 95% confidence interval [CI] 1.67-4.89, and RR 2.01, 95% CI 1.17-3.44, respectively); however, no corresponding differences were observed between ADT + DTX plus darolutamide (DAR) and ADT + DTX (RR 1.55, 95% CI 0.73-3.30, and RR 0.94, 95% CI 0.63-1.40, respectively). For mCRPC assuming a history of mHSPC treatment, ADT + AA + P plus olaparib (OLA) demonstrated a statistically significant decrease in hypertension versus ADT + AA + P (RR 0.20, 95% CI 0.16-0.26). M0CRPC results were unremarkable. CONCLUSIONS AND CLINICAL IMPLICATIONS: For mHSPC, ADT + DTX + DAR demonstrates less cardiotoxicity than ADT + DTX + AA + P due to a lower risk of hypertension and arrhythmias from decreased mineralocorticoid excess. In addition, OLA counterintuitively offers decreased hypertension when superimposed on ADT + AA + P for mCRPC treatment after prior androgen deprivation from mHSPC therapy.

Real-world prevalence, treatment and survival of "high risk" early breast cancer, with mandatory testing of gBRCA1/2 mutation according to the OlympiA trial inclusion criteria: Data from a population-based registry.

BACKGROUND: The results of the OlympiA study led to the approval of a PARP inhibitor (olaparib) as adjuvant treatment for early breast cancer (eBC) at high risk of relapse in patients with a germline BRCA1/2 mutation (gBRCAm). However, the proportion of patients in routine practice who meet the "high-risk" criteria applied in the OlympiA study, and for whom gBRCAm testing would now be mandatory, remains unknown. PATIENTS AND METHODS: In this population-based study, we use unique data from the French specialized Côte d'Or Breast and Gynecological Cancer Registry, to assess the real-life proportion, and long-term prognosis of patients treated for eBC between 2005 and 2015 with standard treatment, and at "high risk" of relapse according to the OlympiA trial criteria. RESULTS: We included 3483 patients treated for HER2-negative eBC (N = 380 with ER-, and N = 3103 with ER + tumor). We found N = 62 (1.8 %) patients with gBRCA1/2 mutations. A total of 494 patients (14.2 %) were classified as "high risk" according to the Olympia criteria; 55 % with ER-tumors, and 9.1 % with ER + tumors, respectively. Despite more intensive systemic treatments in "high risk" patients, 10-year overall survival was much worse in these "high risk" patients compared to the others: 60.1 % vs 83.8 % in ER-tumors, and 55.4 % vs 84.1 % in ER + tumors. Our estimates of net survival show an even greater difference. CONCLUSION: This study provides real-life insights into the prevalence and prognosis of patients with high-risk eBC, in a context where the approval of adjuvant olaparib requires careful reorganization of care, so as not to overlook a patient with gBRCAm who could benefit from adjuvant olaparib.

Efficacy and safety of different regimens of neoadjuvant therapy in patients with hormone receptor-positive, her2-negative breast cancer: a network meta-analysis.

Introduction: The objective of this systematic review and network meta-analysis (NMA) is to assess the effectiveness and safety of various neoadjuvant treatment protocols in individuals diagnosed with hormone receptor-positive, her2 negative(HR+/HER2-) breast cancer. Materials and methods: A systematic search was conducted in four databases (Medline, Embase, Web of Science, and CENTRAL) from the inception of the databases to January 16, 2024, to identify randomized controlled trials (RCTs) to various neoadjuvant therapy options in patients diagnosed with hormone receptor-positive, HER2-negative breast cancer. A network meta-analysis was conducted to evaluate pathological complete response (pCR). Results: There were 17 randomized controlled trials (RCTs) included in the analysis. These trials examined 16 different treatment regimens and involved a total of 5752 participants. The analysis revealed that the six most effective neoadjuvant treatment regimens for HR+/HER2- breast cancer were: CT(A)+olaparib (82.5%), CT(A)+nivolumab (76.5%), Com (74.9%), CT (72.1%), Mono+eribulin (72.0%), and CT(A)+pembrolizumab (70.4%).Paired meta-analysis for pathological complete response (pCR) found no statistically significant distinction between treatment regimens that included both anthracycline and immunosuppressants and regimens that relied solely on anthracycline chemotherapy(OR:1.14, 95%ci 0.79-1.64, I2 = 71%, P=0.50). Similarly, there was no significant difference between platinum-based chemotherapy and anthracycline-basedchemotherapy(OR:1.37, 95%ci 0.53- 3.56, I2 = 11%, P=0.52). With regards to safety, adverse effects of grade 3-5 were observed, which included haematological toxicity, gastrointestinal reactions, skin and mucous membrane reactions, neuropathy, hepatotoxicity, and cardiac disorders. Conclusions: The CT(A)+Olaparib and CT(A)+nivolumab groups demonstrated superior efficacy in neoadjuvant therapy for HR+/HER2- breast cancer. Furthermore, it is crucial to focus on effectively managing the adverse effects of the treatment plan to enhance patient's ability to tolerate it. Given the constraints of the current research, additional well-executed and suitable RCTs are necessary to validate the findings of this investigation. Although pCR is valuable in assessing the effect of neoadjuvant therapy in some cases, prognostic prediction and efficacy assessment in patients with HR+/HER2- breast cancer should be based on a combination of broader clinical and biological characteristics. Systematic review registration: PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024534539, CRD42024501740.

Long-Term Survival in BRCA1 Mutant Advanced Ovarian Cancer: Unveiling the Impact of Olaparib.

Ovarian cancer is one of the most frequent malignancies in women. The treatment landscape underwent significant changes as new agents were introduced in ovarian cancer management over the last decade. We present two cases of long responses to Olaparib in BRCA (BReast CAncer gene) mutant ovarian cancer patients. The first case belongs to a 42-year-old female diagnosed with advanced ovarian carcinoma with a rare germinal mutation (BRCA1 c.68_69delAG, commonly found in descendants of Ashkenazi Jewish populations, but also Arabic and Asian ones) and a significant family history of ovarian and breast cancers. After poorly tolerated neoadjuvant chemotherapy, the patient underwent total hysterectomy, bilateral adnexectomy, and intraperitoneal hyperthermic chemotherapy. After eight months, the disease progressed, and first-line platinum chemotherapy was administered. Although not well-tolerated (grade 3 anemia, allergic reactions), chemotherapy resulted in a partial response, and given the patient's characteristics, maintenance with Olaparib was recommended. Treatment is ongoing (total current duration 69 months) and tolerated well (grade 1 side effects). This case illustrates the long-term benefits that novel therapies like Olaparib may offer in patients with platinum-sensitive relapsed ovarian cancer harboring a rare BRCA mutation. The second case highlights a 55-year-old postmenopausal woman diagnosed with ovarian cancer, FIGO stage IVA. Initial treatment included six cycles of chemotherapy, which led to a partial response, followed by interval debulking surgery and another four cycles of chemotherapy. Subsequent Olaparib maintenance therapy post BRCA1 mutation identification contributed to a significant progression-free survival of 65 months until disease recurrence and secondary cytoreductive surgery, showcasing the effectiveness of PARP inhibitors in personalized oncology treatment of ovarian cancer.

Olaparib combined with CDK12-IN-3 to promote genomic instability and cell death in ovarian cancer.

Large-scale phase III clinical trials of Olaparib have revealed benefits for ovarian cancer patients with BRCA gene mutations or homologous recombination deficiency (HRD). However, fewer than 50% of ovarian cancer patients have both BRCA mutations and HRD. Therefore, improving the effect of Olaparib in HR-proficient patients is of great clinical value. Here, a combination strategy comprising Olaparib and CDK12-IN-3 effectively inhibited the growth of HR-proficient ovarian cancer in cell line, patient-derived organoid (PDO), and mouse xenograft models. Furthermore, the combination strategy induced severe DNA double-strand break (DSB) formation, increased NHEJ activity in the G2 phase, and reduced HR activity in cancer cells. Mechanistically, the combination treatment impaired Ku80 poly(ADP-ribosyl)ation (PARylation) and phosphorylation, resulting in PARP1-Ku80 complex dissociation. After dissociation, Ku80 occupancy at DSBs and the resulting Ku80-primed NHEJ activity were increased. Owing to Ku80-mediated DNA end protection, MRE11 and Rad51 foci formation was inhibited after the combination treatment, suggesting that this treatment suppressed HR activity. Intriguingly, the combination strategy expedited cGAS nuclear relocalization, further suppressing HR and, conversely, increasing genomic instability. Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.

Real-world data on the prevalence of BRCA1/2 and HRR gene mutations in patients with primary and metastatic castration resistant prostate cancer.

PURPOSE: This study seeks to contribute real-world data on the prevalence of BRCA1/2 and HRR gene mutations in prostate cancer. METHODS: We compiled sequencing data of 197 cases of primary and metastatic prostate cancer, in which HRR mutation analysis was performed upon clinical request within the last 5 years. All cases were analyzed using a targeted NGS BRCAness multigene panel, including 8 HRR genes (ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, HDAC2, PALB2). RESULTS: Our findings reveal a prevalence of potentially targetable mutations based on FDA criteria of 20.8%, which is comparable to the literature. However, the frequency of targetable BRCA2 mutations within our cohort was lower than reported for mCRPC and ATM and CHEK2 mutations were more prevalent instead. Thus, while 20.8% (n = 38) of the cases meet the criteria for olaparib treatment per FDA approval, only 4.9% (n = 9) align with the eligibility criteria according to the EMA approval. CONCLUSION: This study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment.

Exploring the impact of BRCA1 and BRCA2 mutation type and location on Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer patients: A single center report.

OBJECTIVE: In patients with platinum-sensitive relapsed ovarian cancer (PSROC) harboring pathogenic/likely pathogenic variants (PV) in BRCA1 and BRCA2 genes, olaparib maintenance monotherapy (OMT) is a viable option. Our study aimed to evaluate the impact of different BRCA1/2 PV in survival outcomes and safety of OMT in BRCA1/2-mutated PSROC patients, focusing on the type and location of PV. METHODS: We assessed the outcomes of 100 BRCA1/2-mutated PSROC patients treated at our institute, analyzing progression-free survival (PFS) and overall survival (OS). Germline and tumor BRCA1/2 genotyping was conducted using Illumina's next-generation sequencing (NGS). RESULTS: PFS and OS were significantly shorter in PSROC patients with PV in BRCA1 compared to those with PV in BRCA2 (PFS:14.0 vs. 38.8 months, p = 0.007, OS: 21.8 vs. 62.0 months, p = 0.011). Notably, there was a significant difference in PFS based on the intragenic location of BRCA1 PV, with shorter PFS in patients with 1st/2nd relapse, harboring PV in BRCA1 RING domain compared to those with PV in the DNA binding domain (DBD) and BRCT domains (12.4 vs. 23.0 months, p = 0.046). No differences in PFS and OS were observed between patients with germline versus somatic BRCA1/2 PV (PFS:14.9 vs.19.3, p = 0.316, OS: not reached vs. 25.8 months; p = 0.224). However, there were significant differences in the reasons for OMT discontinuation between patients with germline and somatic BRCA1/2 PV, primarily due to adverse side effects. CONCLUSIONS: In summary, the type and location of BRCA1 and BRCA2 PV provide additional insight into the expected survival outcomes of olaparib MT in PSROC patients. TRIAL REGISTRATION NUMBER: ISRCTN42408038, Name of registry: ISRCTN registry, Date of registration: 24/11/2015.

Olaparib induced aplastic anemia in a patient with castrate resistant prostate cancer: A case report.

Olaparib is (ADP-ribose) polymerase inhibitor (PARPi), which stops the repair of single-stranded DNA breaks. This leads to the death of cancer cells with BRCA1/BRCA2 mutations or homologous recombination deficiency. Since being approved by the FDA in 2023 for treating castrate-resistant prostate cancer (CRPC), there have been some reports of myelodysplastic syndrome (MDS) and acute leukemia linked to PARP inhibitor use for ovarian, breast, pancreatic and breast cancers, there have been no reports of aplastic anemia after receiving PARPi therapy. This case report describes a 75-year-old man with BRCA2-positive metastatic castrate-resistant prostate cancer who developed aplastic anemia after taking olaparib.

Low-dose abiraterone plus Olaparib as a late-line treatment for mCRPC patients without BRCA1/2 mutations: a multicenter retrospective pilot study.

Although overall survival data are still premature, the PROpel study found radiological progression-free survival (PFS) benefits of abiraterone and olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). However, for patients who have not been genetically tested or lack BRCA1/2 mutations (BRCAm), this combination therapy has been questioned as a first-line conventional treatment for mCRPC, mainly due to significant health economics and side effects. In our retrospective study, we found that treatment with low-dose abiraterone plus olaparib as a late-line treatment for mCRPC could lead to prostate-specific antigen (PSA) and symptom PFS in selective cases even without BRCAm. The median PSA-PFS was 8 months (IQR: 6.5-11.5), with a median follow-up duration of 39.0 months (IQR: 27.5-64.5). Gene tests were conducted in all patients, identifying non-BRCA mutations through ctDNA testing (24%), tumor tissue testing (12%), or both (64%). Adverse events occurred in 72% of patients, with 16% experiencing Grade ≥ 3 events. Common adverse events included anemia (64%), decreased appetite (48%), and fatigue (25%). Our findings support low-dose abiraterone plus olaparib as a potential option for mCRPC patients without BRCAm, offering manageable safety and efficacy profiles.

Olaparib monotherapy or in combination with abiraterone for treating mutated metastatic castration-resistant prostate cancer: alone or stronger together?

INTRODUCTION: Prostate cancer has entered the era of precision medicine with the introduction of PARP inhibitors for patients with specific mutations in genes associated with DNA damage repair. Recent studies have shown benefit in combination therapy with PARP inhibitors like olaparib and antiandrogens like abiraterone. AREAS COVERED: This review discusses the pharmacodynamics and pharmacokinetics of olaparib as well as the data supporting combination therapy with olaparib and abiraterone. EXPERT OPINION: Co-targeting the androgen receptor and PARP pathway has shown clear clinical benefit in the management of patients with metastatic castration resistant prostate cancer and mutations in BRCA1, BRCA2, and ATM. The benefit in patients without these mutations is less clear, and the benefit of olaparib combination therapy in the management of hormone sensitive disease remains to be seen.

Case Report of Complete Response to Olaparib in a Patient with Breast Cancer Brain Metastases.

Introduction: Breast cancer is the second most common cause of central nervous system (CNS) metastases. It has been shown that the median time from breast cancer diagnosis to CNS metastasis is 30.9 months and that the overall median survival after metastasis is extremely poor at 6.8 months. Although treatment options for ErbB2 Receptor Tyrosine Kinase 2 (ERBB2)-positive breast cancer brain metastasis (BCBM) have been reported, effective treatment options for ERBB2-negative BCBM, which has one of the worst prognoses, are limited. Olaparib is one of the standard treatments for germline BRCA1/2 mutated (gBRCA1/2mt), ERBB2-negative, metastatic, or recurrent breast cancer. However, there is minimal existing evidence to evaluate the efficacy of olaparib in BCBM. Case Presentation: In our report, we assessed the case of a Japanese woman in her early 30s, ERBB2-negative, gBRAC2mt-positive BCBM, who achieved a complete response and prolonged progression-free survival of 9 months after the initiation of treatment with olaparib. Conclusions: Thus, our case report demonstrated the significant efficacy of olaparib in BCBM treatment. Furthermore, we highlighted the need for more studies to investigate the efficacy of olaparib and explore the efficacy of poly ADP ribose polymerase inhibitors in BCBM.

Role of poly-ADP-ribose polymerase inhibitors after brain progression in platinum-sensitive ovarian cancer: a case report and review of the literature.

Introduction: The incidence of brain metastases in ovarian cancer is quite rare, being approximately 1%-2%. According to retrospective studies, patients with BRCA 1/2 mutations present a higher risk. The trimodal approach based on surgery, radiotherapy, and chemotherapy presents better outcomes, but the prognosis remains poor with overall survival since the brain progression is around 1 year. Poly-ADP-ribose polymerase inhibitors (PARPi) have provided a new alternative for the management of advanced ovarian cancer. The SOLO2, NOVA, and ARIEL3 clinical trials do not refer data on patients with brain metastases, and the published evidence for PARPi in this setting comes only from case reports and retrospective studies. Case report: We present the case of a 54-year-old woman with stage IV ovarian high-grade serous papillary carcinoma who, after 37 months of treatment with olaparib, presented a single brain lesion. After radical treatment with surgery and adjuvant whole-brain radiotherapy, she resumed olaparib with no evidence of disease during 15 months. After a second single brain relapse treated with stereotactic radiosurgery, the patient continued olaparib beyond the brain progression with no evidence of extracranial disease. Despite that there were no changes in size or number of brain lesions, the neurological situation progressively worsened and the patient died 8 months after the second progression. Discussion: The higher incidence of brain metastases of ovarian cancer points out a possible tropism for the CNS in BRCA-mutated patients. In preclinical studies, PARPi has shown to cross the blood-brain barrier, with possible antitumor activity in the central nervous system (CNS) while maintaining control of extracranial disease. The best survival data are obtained with a trimodal approach, and adding a PARPi could improve the survival outcomes in the context of platinum-sensitivity disease. Targeted therapies combined with local treatments are also used in other malignancies, suggesting potential effectiveness due to tumor heterogeneity. PARPi before brain metastasis may delay its diagnosis, and using iPARP after brain metastases could improve the outcome of this population. Conclusion: The role that PARPi may have in the treatment of brain metastases of ovarian cancer requires more studies. In the context of radical treatment of brain metastasis (surgery and/or RT), with no evidence of extracranial disease, maintaining treatment with PARPi beyond the brain progression should be considered.

DNA damage induced PARP-1 overactivation confers paclitaxel-induced neuropathic pain by regulating mitochondrial oxidative metabolism.

AIMS: Poly (ADP-ribose) polymerase (PARP) has been extensively investigated in human cancers. Recent studies verified that current available PARP inhibitors (Olaparib or Veliparib) provided clinical palliation of clinical patients suffering from paclitaxel-induced neuropathic pain (PINP). However, the underlying mechanism of PARP overactivation in the development of PINP remains to be investigated. METHODS AND RESULTS: We reported induction of DNA oxidative damage, PARP-1 overactivation, and subsequent nicotinamide adenine dinucleotide (NAD+) depletion as crucial events in the pathogenesis of PINP. Therefore, we developed an Olaparib PROTAC to achieve the efficient degradation of PARP. Continuous intrathecal injection of Olaparib PROTAC protected against PINP by inhibiting the activity of PARP-1 in rats. PARP-1, but not PARP-2, was shown to be a crucial enzyme in the development of PINP. Specific inhibition of PARP-1 enhanced mitochondrial redox metabolism partly by upregulating the expression and deacetylase activity of sirtuin-3 (SIRT3) in the dorsal root ganglions and spinal cord in the PINP rats. Moreover, an increase in the NAD+ level was found to be a crucial mechanism by which PARP-1 inhibition enhanced SIRT3 activity. CONCLUSION: The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment.

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study.

PURPOSE: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). METHODS: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. RESULTS: A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4-99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7-94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. CONCLUSIONS: This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.