Pacientce s primárně pokročilým karcinomem vaječníků, u níž nebylo možno ani přes extenzivní chirurgický výkon dosáhnout nulového pooperačního rezidua nádoru, a která tak spadá do kategorie žen s vysokým rizikem relapsu onemocnění, byla v rámci adjuvantní léčby nabídnuta aplikace nejen standardní cílené léčby (bevacizumabu), ale s ohledem na molekulární vyšetření nádoru i výsledek germinálního testování i aplikace udržovací léčby inhibitorem poly (adenosin difosfát-ribóza) polymerázy (PARP) olaparibem. Léčba byla aplikována bez nežádoucích účinků nebo příhod. Rok od zahájení léčby pacientka žije s vynikající kvalitou života bez známek nádorového onemocnění.

A patient with primarily advanced ovarian cancer, in whom it was not possible to achieve zero postoperative tumor residue despite extensive surgery and who therefore falls into the category of women at high risk of disease relapse, was offered not only standard targeted therapy (bevacizumab) as part of adjuvant treatment, but also, based on molecular tumor testing and germline testing results, maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. The treatment was administered without adverse effects or incidents. One year after the start of treatment, the patient is living with an excellent quality of life and no signs of cancer.

Metastazující kastračně rezistentní karcinom prostaty (metastatic castration resistant prostate cancer, mCRPC) představuje nejzávažnější formu široké skupiny karcinomů prostaty. Je typický rezistencí k primární androgen deprivační terapii, proto je pro účinnou léčbu nutné rozšířit léčebné spektrum. Čím více linií terapie použijeme, tím lze život pacientů s mCRPC více prodloužit. Jednou z léčebných možností je i cílená léčba. Inhibitory poly(ADP-ribóza) polymerázy (PARP) prokázaly u těchto pacientů účinnost jednak v monoterapii, jednak v kombinaci s léčbou cílenou na androgenní receptor. Článek se věnuje postavení inhibitoru PARP talazoparibu v léčbě mCRPC.

Metastatic castration resistant prostate cancer (mCRPC) represents the most severe form of a group of prostate cancer. It is characterized by resistance to primary androgen deprivation therapy, which necessitates the expansion of the treatment spectrum for effective management. The more lines of therapy we use, the more we can prolong the survival of patients with mCRPC. One of the treatment options is targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated efficacy, both in monotherapy and in combination with androgen receptor targeted therapy in these patients. The article discusses the role of the PARP inhibitor talazoparib in the treatment of mCRPC.

Základem léčby pokročilého karcinomu prostaty je hormonální terapie, která ale u pacientů s mutacemi v genech pro opravy DNA ztrácí účinnost. Tyto mutace se vyskytují u téměř 30 % pacientů s diseminovaným karcinomem prostaty; nejčastěji se jedná o mutace v genech BRCA. Pomocí sekvenování nové generace jsme schopni tyto pacienty identifikovat a nabídnout jim účinnou cílenou léčbu inhibitory poly(adenosindifosfát-ribóza) polymerázy (PARP). Článek popisuje mechanismus účinku PARP inhibitorů, zaměřuje se na významné klinické studie s olaparibem, na jeho přínosy a nežádoucí účinky.

Hormone therapy is the cornerstone of treatment for advanced prostate cancer. However, it loses effectiveness in patients with mutations in DNA repair genes. These mutations are found in nearly 30% of patients with disseminated disease, the most common are BRCA mutations. Using next generation sequencing (NGS) testing, we can identify these patients and offer them effective targeted treatment with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. This article describes the mechanism of action of PARP inhibitors, focusing on key clinical trials involving olaparib, along with its benefits and side effects.

Diagnostika a terapie karcinomu prsu se posouvají stále kupředu. Zvláštní skupinou pacientek jsou pacientky s germinální mutací v genech BRCA1 a BRCA2. U nádorů s germinální mutací BRCA se vyskytují všechny fenotypy karcinomu prsu. S ohledem na funkci reparačních genů přináší tato mutace vyšší chemosenzitivitu na cytostatika působící porušení DNA a také na inhibitory poly(ADP-ribóza) polymerázy (PARP). Právě podání inhibitorů PARP přináší nadějné výsledky. Přípravek talazoparib se stává nadějí u metastazujícího onemocnění při dobré kvalitě života pacientek.

Diagnosis and therapy of breast cancer is constantly moving forward. A special group of patients are with germ cell mutations BRCA1 and BRCA2. In tumors with a BRCA germ cell mutation, all phenotypes of breast cancer are present. Regarding the function of repair genes, this mutation brings higher chemosensitivity to cytostatic causing DNA damage and to poly[ADP-ribose] polymerase inhibitors (PARP). It is the administration of PARP inhibitors that brings promising results. Talazoparib is becoming a hope in metastatic disease with a good quality of life in patients.

Duktální adenokarcinom slinivky břišní (PDAC) je agresivní onemocnění, jehož incidence v populaci narůstá a do budoucna i výrazně narůstat bude. I přes veškerou snahu 5leté přežívání pacientů s PDAC obvykle nepřesahuje 10 %. Základem léčby prakticky v jakémkoliv stadiu je hlavně chemoterapie. Ostatní modality léčby se bohužel dají využívat jen ojediněle. Jednu takovou zřídkavou možnost představuje použití inhibitorů PARP, v České republice konkrétně hlavně olaparibu, u pacientů s nádory slinivky břišní s mutací BRCA, kteří dle indikace neprogredují při chemoterapii s platinovým derivátem. Nynější výsledky však naznačují, že by indikace této dobře snášené léčby měly být rozšířeny na větší populaci pacientů.

Pancreatic ductal adenocarcinoma (PDAC) is aggressive disease with permanently rising incidence in population. We also expect further growth in the near future. Despite all efforts, the 5year survival of our patients with PDAC usually does not exceed 10 %. The basis of treatment at any stage is mainly chemotherapy. Unfortunately, other modalities can only be used in rare cases. One such situation is represented by PARP inhibitors, in the Czech Republic particularly by olaparib, intended for patients with advanced PDAC not progressing during the platinumbased chemotherapy. Current results suggest that this well-tolerated treatment could be provided to broader spectrum of patients.

PURPOSE OF REVIEW: Recent advancements in the understanding of the genetic background of genitourinary cancers allowed for a successful introduction of targeted antitumor agents to prostate cancer (PCa) treatment. Inhibitors of the poly ADP-ribose polymerase enzyme (PARPi) transformed the treatment landscape of metastatic prostate cancer, and being increasingly studied in earlier disease stages. However, they are associated with nonnegligible toxicity, therefore, we aimed to summarize their side-effect profile in patients with PCa. RECENT FINDINGS: Hematologic toxicities, particularly anemia, thrombocytopenia, and neutropenia are among the most common and serious adverse events associated with PARPi, highlighting the need for regular blood count monitoring. Nonhematologic side effects, including fatigue, nausea, vomiting, diarrhea, and constipation, are common, and can be mitigated with supportive interventions like dietary modifications, antiemetics, or stool management techniques. Special attention should be given to patients with therapy-resistant or persistent cytopenia, in whom bone marrow biopsy should be considered, as it can indicate myelodysplastic syndrome and acute myeloid leukemia. SUMMARY: PARP inhibitors represent a major advancement in the management of metastatic prostate cancer, offering a significant survival benefit in applicable cases. However, patients need to be carefully selected and informed, to allow for optimal balancing between the benefits and nonneglectable risks of severe toxicities. Better understanding of PARPi toxicity profile can improve personalized decision-making and enhance treatment compliance, through raising patients' awareness about the possible side effects of PARPi.

• MeSH
• Humans MeSH
• Prostatic Neoplasms * drug therapy   pathology   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * adverse effects   MeSH
• Urogenital Neoplasms * drug therapy   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX and caspase-3/7 activity. Both HCC cell lines exhibited heightened sensitivity to the combined treatment. The effect of drugs on the expression of proliferation markers in an olaparib-resistant patient-derived xenograft (PDX) model of ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by a drop in proliferation marker Ki-67 levels in response to PARPi combined with CHK1i. No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles.

• MeSH
• Apoptosis drug effects   MeSH
• Hep G2 Cells MeSH
• Checkpoint Kinase 1 metabolism   antagonists & inhibitors   MeSH
• Phthalazines * pharmacology   MeSH
• Carcinoma, Hepatocellular * drug therapy   pathology   metabolism   MeSH
• Liver drug effects   pathology   metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Liver Neoplasms * drug therapy   pathology   metabolism   MeSH
• Ovarian Neoplasms * drug therapy   pathology   metabolism   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors pharmacology   therapeutic use   MeSH
• Piperazines * pharmacology   MeSH
• DNA Damage drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   therapeutic use   adverse effects   MeSH
• Pyrazoles pharmacology   MeSH
• Pyrimidines MeSH
• Drug Synergism * MeSH
• Cell Survival drug effects   MeSH
• Xenograft Model Antitumor Assays * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Poly (ADP ribose) polymerase inhibitors (PARPis) are a treatment option for patients with advanced high-grade serous or endometrioid ovarian carcinoma (OC). Recent guidelines have clarified how homologous recombination deficiency (HRD) may influence treatment decision-making in this setting. As a result, numerous companion diagnostic assays (CDx) have been developed to identify HRD. However, the optimal HRD testing strategy is an area of debate. Moreover, recently published clinical and translational data may impact how HRD status may be used to identify patients likely to benefit from PARPi use. We aimed to extensively compare available HRD CDx and establish a worldwide expert consensus on HRD testing in primary and recurrent OC. METHODS: A group of 99 global experts from 31 different countries was formed. Using a modified Delphi process, the experts aimed to establish consensus statements based on a systematic literature search and CDx information sought from investigators, companies and/or publications. RESULTS: Technical information, including analytical and clinical validation, were obtained from 14 of 15 available HRD CDx (7 academic; 7 commercial). Consensus was reached on 36 statements encompassing the following topics: 1) the predictive impact of HRD status on PARPi use in primary and recurrent OC; 2) analytical and clinical validation requirements of HRD CDx; 3) resource-stratified HRD testing; and 4) how future CDx may include additional approaches to help address unmet testing needs. CONCLUSION: This manuscript provides detailed information on currently available HRD CDx and up-to-date guidance from global experts on HRD testing in patients with primary and recurrent OC.

• MeSH
• Delphi Technique MeSH
• Homologous Recombination MeSH
• Consensus * MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Ovarian Neoplasms * genetics   diagnosis   drug therapy   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection. Analysis of BRCA1/2 status showed that in our cohort of 31 ovarian cancer PDX models 22.6% harbored a BRCA1/2 alteration (7/31), and 48.3% (15/31) were genomically unstable as measured by copy number alteration analysis. In vivo, PARPi olaparib response was measured in 15 selected PDX models. Functional assessment of HR using ex vivo irradiation-induced RAD51 foci formation identified all olaparib-sensitive PDX models, including four models without BRCA1/2 alterations. In contrast, replication fork protection or replication speed in ex vivo tumor tissue did not correlate with olaparib response. Targeted panel sequencing in olaparib-sensitive models lacking BRCA1/2 alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that ex vivo RAD51 analysis effectively predicts in vivo olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.

• Publication type
• Journal Article MeSH

• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   MeSH
• DNA-Directed DNA Polymerase genetics   metabolism   MeSH
• DNA Primase genetics   metabolism   MeSH
• Extracellular Matrix metabolism   pathology   MeSH
• Genes, p53 genetics   MeSH
• Glioblastoma metabolism   pathology   MeSH
• Pericytes metabolism   pathology   MeSH
• BRCA1 Protein genetics   metabolism   MeSH
• Publication type
• Overall MeSH