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Aim: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer (BC) characterized by the lacking estrogen receptors, progesterone receptors, and HER2 expression, making it challenging to treat with targeted therapies. Olaparib, a PARP inhibitor, has shown promise in treating TNBC, particularly in patients with BRCA1 or BRCA2 mutations. This study aims to elucidate the metabolic pathways affected by olaparib in TNBC using bioinformatics analysis. Material and Method: For bioinformatics analysis, mRNA microarray data of control MDA-MB-468 cells (non-treated) and OlaR MDAMB- 468 (3µM olaparib-treated MDA-MB-468 cells) with the study numbered GSE165914 were downloaded from Gene Expression Omnibus (GEO) database. GEO2R was used to analyze and identify differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto gene and genome encyclopedia (KEGG) analysis were carried out for DEGs to determine significant genes and the biological pathways influenced by olaparib treatment. Protein-protein interaction (PPI) network analysis further identified key proteins and interactions within these pathways. Results: For GEO2R analysis adjusted P-value<0.05 and |log2FC|>1.0 were selected. The results revealed the upregulation of 2277 genes and downregulation of 2298 genes in olaparib-treated cells compared to the controls. It was reported that DEGs enriched in pathways including, metabolic pathways, pathways in cancer, chemical carcinogenesis - reactive oxygen species, cell cycle, autophagy - animal, Efferocytosis and TNF signaling pathway. Both upregulated and downregulated DEGs were associated with metabolic pathways. Moreover, NDUFA5, NDUFA6, NDUFS6, NDUFB3, NDUFB10, NDUFB7, NDUFA7, NDUFA9, H2AC8, H2AC13, H2AC17, H4C11, H4C12, H2BC12, H2BC21 and H2BC4 were identified as the most significant candidate genes. Conclusion: This comprehensive bioinformatics approach provides insights into the molecular mechanisms of olaparib's action and identifies potential targets for combination therapies to enhance treatment efficacy in breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Prostate cancer (PCa) is a leading malignancy among men globally, with rising incidence rates emphasizing the critical need for better detection and therapeutic approaches. The roles of HSP90AB1 and PARP1 in prostate cancer cells suggest potential targets for enhancing treatment efficacy. Methods This study investigated the overexpression of HSP90AB1 and PARP1 in prostate cancer cells and the impact of HSP90AB1 knockdown on the sensitivity of these cells to the PARP inhibitor olaparib. We also explored the combined effect of olaparib and celastrol, an HSP90 inhibitor, on the clonogenic survival, migration, proliferation, and overall viability of prostate cancer cells, alongside the modulation of the PI3K/AKT pathway. An in vivo PC3 xenograft mouse model was used to assess the antitumor effects of the combined treatment. Results Our findings revealed significant overexpression of HSP90AB1 and PARP1 in prostate cancer cells. Knockdown of HSP90AB1 increased cell sensitivity to olaparib. The combination of olaparib and celastrol significantly reduced prostate cancer cell survival, migration, proliferation, and enhanced cumulative DNA damage. Celastrol also downregulated the PI3K/AKT pathway, increasing cell susceptibility to olaparib. In vivo experiments demonstrated that celastrol and olaparib together exerted strong antitumor effects. Conclusions The study indicates that targeting both HSP90AB1 and PARP1 presents a promising therapeutic strategy for prostate cancer. The synergistic combination of celastrol and olaparib enhances the efficacy of treatment against prostate cancer, offering a potent approach to combat this disease.

Abstract 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.

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.

Olaparib, an oral poly-ADP ribose polymerase (PARP) inhibitor, is a relatively new anticancer drug. It is essential to find TDM-guided dosage for better safety and tolerability of patients. However, first, it is important to develop a suitable analytical method to conduct reliable TDM. The aim of the study was the validation of UPLC-MS/MS method for TDM of olaparib in patients with ovarian cancer, with a particular attention to optimization of recovery. The validation of the method under analysis were accomplished by the ICH guidelines. The recovery of olaparib was optimized with the Central Composite Design (CCD). The TDM study was conducted on 10 patients with ovarian cancer treated with olaparib. The method validation was characterized by good precision (CV

A 74-year-old woman, who had been receiving olaparib for the treatment of ovarian cancer for more than a year, visited the emergency department complaining of a fever that had lasted for 1 month. She had been taking antipyretics and antibiotics for her fever, but without any effect. Although she had no symptoms other than fever, she had stopped taking olaparib for 1 week before her visit because she had developed anemia caused by myelosuppression from olaparib. After discontinuing olaparib, her maximum body temperature decreased. On admission, chest X-ray revealed no abnormalities, but chest CT showed diffuse ground-glass opacities. Chest CT taken 5 days later showed partial improvement; therefore, we diagnosed her with interstitial lung disease (ILD) associated with olaparib. After short-term steroid treatment, the ground-glass opacities disappeared, and the patient became afebrile. The CT scan taken for tumor evaluation 2 days before the onset of fever showed a few centrilobular nodular opacities and small patchy ground-glass opacities. These findings could indicate early lesions of ILD, but they seemed inconspicuous and nonspecific, and it might have been difficult to diagnose ILD then. To date, few cases of ILD associated with olaparib have been reported. However, based on previous reports, fever is often seen, and CT findings mainly comprise diffuse ground-glass opacities, and in some cases, centrilobular nodular shadows. Thus, in conjunction with the findings of the present case, these characteristics may be representative of olaparib-induced ILD.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9–89.6%) and median PFS was 16.4 months (95% CI 13.2–18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3–18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4–40.1%) with median PFS 6.8 months (95% CI 4.2–9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6–7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting. • Combination cediranib/olaparib has clinical activity in relapsed platinum sensitive and resistant ovarian cancer. • Mutations in homologous recombination repair genes were not associated with clinical activity of cediranib/olaparib. • Exploratory analysis of loss of heterozygosity did not demonstrate association with activity of cediranib/olaparib. [ABSTRACT FROM AUTHOR]

This article discusses a case study on the treatment of relapsed acute myeloid leukemia (AML) in an elderly patient with the AML1:ETO fusion gene. The patient achieved remission initially but relapsed a year later. Whole-exome sequencing revealed mutations in genes associated with DNA repair, suggesting a potential benefit from PARP inhibitor (PARPi) treatment. The patient received olaparib in combination with low-dose chemotherapy and achieved complete remission. In vitro experiments also showed the synergistic effect of olaparib and decitabine on AML1:ETO leukemia cell lines. The article suggests that this treatment approach may be promising for relapsed AML1:ETO-positive leukemia, particularly in elderly patients, but further clinical trials are needed for validation. [Extracted from the article]

The present study aimed to clarify the hypothesis that auger emitter 125I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression by promoting antitumor immune response. Pancreatic cancer cell line (Panc02) and mice subcutaneously inoculated with Panc02 cells were employed for the in vitro and in vivo experiments, respectively, followed by 125I and Olaparib administrations. The apoptosis and CRT exposure of Panc02 cells were detected using flow cytometry assay. QRT-PCR, immunofluorescence, immunohistochemical analysis, and western blot were employed to examine mRNA and protein expression. Experimental results showed that 125I combined with Olaparib induced immunogenic cell death and affected antigen presentation in pancreatic cancer. 125I in combination with Olaparib influenced T cells and dendritic cells by up-regulating CD4, CD8, CD69, Caspase3, CD86, granzyme B, CD80, and type I interferon (IFN)-γ and down-regulating Ki67 in vivo. The combination also activated the cyclic GMP-AMP synthase stimulator of IFN genes (Sting) pathway in Panc02 cells. Moreover, Sting knockdown alleviated the effect of the combination of 125I and Olaparib on pancreatic cancer progression. In summary, 125I in combination with Olaparib inhibited pancreatic cancer progression through promoting antitumor immune responses, which may provide a potential treatment for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Thyroid cancer incidence increases worldwide annually, primarily due to factors such as ionizing radiation (IR), iodine intake, and genetics. Papillary carcinoma of the thyroid (PTC) accounts for about 80% of thyroid cancer cases. RET/PTC1 (coiled‐coil domain containing 6 [CCDC6]‐rearranged during transfection) rearrangement is a distinctive feature in over 70% of thyroid cancers who exposed to low doses of IR in Chernobyl and Hiroshima‒Nagasaki atomic bombings. This study aims to elucidate mechanism between RET/PTC1 rearrangement and IR in PTC. N‐thy‐ori‐3‐1 cells were subjected to varying doses of IR (2/1/0.5/0.2/0.1/0.05 Gy) of IR at different days, and result showed low‐dose IR‐induced RET/PTC1 rearrangement in a dose‐dependent manner. RET/PTC1 has been observed to promote PTC both in vivo and in vitro. To delineate the role of different DNA repair pathways, SCR7, RI‐1, and Olaparib were employed to inhibit non‐homologous end joining (NHEJ), homologous recombination (HR), and microhomology‐mediated end joining (MMEJ), respectively. Notably, inhibiting NHEJ enhanced HR repair efficiency and reduced IR‐induced RET/PTC1 rearrangement. Conversely, inhibiting HR increased NHEJ repair efficiency and subsequent RET/PTC1 rearrangement. The MMEJ did not show a markable role in this progress. Additionally, inhibiting DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) decreased the efficiency of NHEJ and thus reduced IR‐induced RET/PTC1 rearrangement. To conclude, the data suggest that NHEJ, rather than HR or MMEJ, is the critical cause of IR‐induced RET/PTC1 rearrangement. Targeting DNA‐PKcs to inhibit the NHEJ has emerged as a promising therapeutic strategy for addressing IR‐induced RET/PTC1 rearrangement in PTC. [ABSTRACT FROM AUTHOR]

A 73-year-old Japanese man with a history of distal biliary cancer treated by pancreatoduodenectomy developed pancreatic acinar cell carcinoma (PACC) treated by remnant pancreatectomy and adjuvant chemotherapy. Thirteen months after surgery, multiple liver metastases developed and FOLFOX chemotherapy was initiated. Based on the PACC diagnosis and a positive family history for breast and ovarian cancer genetic testing was performed which revealed a pathogenic germline BRCA2 variant (c.8629G > T, p.Glu2877Ter). Olaparib therapy was initiated and the metastases responded well (partial response). PACC is a BRCA2-associated cancer which may respond well to PARP inhibitors. [ABSTRACT FROM AUTHOR]

Background: With recent dramatic developments in chemotherapy, attempts to incorporate surgery into the multidisciplinary treatment of unresectable pancreatic ductal adenocarcinoma with metastasis (UR-M PDAC) have emerged. Maintenance therapy with olaparib after chemotherapy including a platinum-based regimen, which inhibits the poly ADP-ribose polymerase (PARP) involved in DNA repair, was approved for UR-M PDAC with positive BRCA mutations. Case presentation: A 47-year-old male patient with a high carbohydrate antigen 19-9 (CA19-9) level was diagnosed with PDAC in the pancreatic tail. Staging laparoscopy revealed occult liver metastasis. Because BRCA2 mutation was confirmed, triple combination chemotherapy with SOXIRI (S-1/oxaliplatin/irinotecan) was introduced and continued for 16 weeks, followed by 14 weeks of olaparib. After that, CA19-9 was normalized, and no obvious liver metastases of any size could be seen on imaging studies during chemotherapy. Since staging laparoscopy after chemotherapy proved that the liver metastasis had disappeared, laparoscopic distal pancreatectomy was performed, and curative resection was completed. After adjuvant chemotherapy with olaparib for 12 months, the patient is alive 36 months from his initial diagnosis and 27 months postoperatively without recurrence. Conclusion: We report a case of PDAC with liver metastasis and BRCA mutation-positivity who underwent conversion surgery and achieved long-term survival after irinotecan-based chemotherapy followed by maintenance therapy with olaparib. [ABSTRACT FROM AUTHOR]