PARP Inhibitors In Patients Research Articles

Re-treatment with PARPi in patients with recurrent epithelial ovarian cancer: A single institutional experience

IntroductionWe aimed to evaluate real-life experiences with the re-challenge of poly(ADP-Ribose)Polymerase (PARP) inhibitors (PARPi) after a prior PARPi therapy in patients with recurrent EOC. MethodsA retrospective descriptive study was conducted at a tertiary care center of excellence for ovarian cancer. Demographic, pathological, and therapeutic data were collected for patients with recurrent epithelial ovarian cancer who were re-treated with PARPi in their therapy course. ResultsTwenty-nine patients were included in the study. Twenty-six patients received the second PARPi as maintenance therapy after two different lines of therapy and three patients received the second PARPi as upfront therapy after progression. Most of the patients (57.7%) were exposed to first PARPi after a second-line therapy. The median progression-free survival under the first and second PARPi therapy was estimated at 15 and 7 months respectively. PFS under the second PARPi after platinum-based chemotherapy was better after a complete remission with a median PFS of 8.5 months, compared to patients with partial remission (5.5 months). A better PFS was noted in case of negative BRCA status under the second PARPi therapy (median PFS of 7.4 vs. 4.5 months, p = 0.11). The second PARPi therapy was mainly discontinued due to disease progression (84.6% of the cases). Discontinuation of treatment with the second PARP due to toxicity was needed in one case who developed a myelodysplastic syndrome. ConclusionReal-life data support prospective evidence that patients with recurrent EOC may derive benefit of the re-treatment with PARPi in case of clear response to the last platinum-based therapy.

Randomized Clinical Trials and Real World Prospective Observational Studies on Bevacizumab, PARP Inhibitors, and Immune Checkpoint Inhibitors in the First-Line Treatment of Advanced Ovarian Carcinoma: A Critical Review.

Platinum/paclitaxel-based chemotherapy is able to obtain a clinical response in up to 80% of patients with advanced ovarian carcinoma, but most of them will subsequently develop recurrent disease. Several therapeutic approaches, including prolonged administration of the first-line regimen and the concomitant or sequential addition of a third cytotoxic agent to standard chemotherapy, failed to improve the clinical outcome of patients. In the last years, the implementation of the biological knowledge on ovarian carcinoma and the introduction of bevacizumab (BEV) and poly(ADP-ribose) polymerase inhibitors (PARPi) in first-line treatment have improved patient prognosis. In this review, we have analyzed the randomized clinical trials and real world observational studies on these issues, with the aim to suggest an algorithm for a rational use of BEV and PARPi in patients with newly diagnosed advanced ovarian carcinoma.

Synthetic Lethality in Ovarian Cancer.

Ovarian cancers include several distinct malignancies which differ with respect to clinicopathologic features and prognosis. High-grade serous cancer is the most common histologic subtype and accounts for most ovarian cancer-related deaths. High-grade serous ovarian cancer (HGSOC) is treated with surgery and platinum-based chemotherapy, but most patients relapse and succumb to chemoresistant disease. The genetic concept of synthetic lethality, in which the synergy of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to overcome chemoresistance in ovarian cancer. Recent progress in understanding the genomic architecture and hereditary drivers of ovarian cancer has shown potential for synthetic lethality strategies designed around homologous DNA repair. Clinical trials have validated high response rates for PARP inhibitors in patients with BRCA1 or BRCA2 mutations. Here we discuss the biological rationale behind targeting BRCA-PARP synthetic lethality based on genetic context in ovarian cancer and how this approach is being assessed in the clinic. Applying the concept of synthetic lethality to target non-BRCA-mutant cancers is an ongoing challenge, and we discuss novel approaches to target ovarian cancer using synthetic lethality in combination with and beyond PARP inhibitors. This review will also describe obstacles for synthetic lethality in ovarian cancer and new opportunities to develop potent targeted drugs for patients with ovarian cancer.

Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update.

ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.

A phase II study of rucaparib in patients with high genomic LOH and/or BRCA 1/2 mutated stage IV non-small cell lung cancer (Lung-MAP Sub-Study, S1900A).

9024 Background: While prior studies have shown robust efficacy leading to FDA approval of PARP inhibitors (PARPi) in BRCA-associated cancers, data in NSCLC are much less clear. S1900A, a LUNG-MAP substudy, evaluated the PARPi rucaparib in advanced stage NSCLC harboring BRCA1/2 mutations or genomic loss of heterozygosity (LOH) as a phenotypic marker of homologous recombination deficiency (HRD). Methods: Eligible patients (pts) were required to have a deleterious mutation in BRCA1/BRCA2 and/or high (≥21%) genomic LOH. Key eligibility criteria: advanced NSCLC patients (pts) with progression on or after platinum based chemotherapy and/or PD-(L)1 antibody and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, no ≥ grade 3 hypercholesterolemia, no previous PARPi exposure and no systemic therapy within 21 days of registration. Pts stratified by histology into two cohorts (squamous [sq] and non-squamous/mixed histology [nsq]). With 40 eligible pts per cohort, the design had 91% power to rule out an ORR of 15% if the true ORR was at least 35% at the 1-sided 5% level. A planned interim analysis on the first 20 pts evaluable for response per cohort required ≥ 3 responses to proceed to full enrollment. Results: 64 pts enrolled (27 sq cohort; 37 nsq cohort) of whom 59 are eligible. Median age 65.7 yrs; M/F 33/26 (56/44%); 98% of the pts received at least 1 prior line of treatment for stage IV disease. Biomarker selection included 36 pts (61%) LOH only, 4 pts (7%) BRCA1 only, 11 pts (19%) BRCA2 only, 4 pts (7%) BRCA1 + LOH high and 4 pts (7%) BRCA2 + LOH high. Both cohorts were closed for futility with insufficient responses in the interim analysis populations. In the full study, 4 responses (3 nsq/1 sq) were reported. ORR was 7% (95% CI: 0-13) (9% nsq/4% sq) and DCR was 62% (95% CI: 50-75) (62% nsq/64% sq); 3 of the 4 responders harbored BRCA1/2 mutations and 1 of 4 high LOH; ORR in BRCA1/2+ pts 3/23 (13%). Median PFS was 3.2 months (95% CI: 1.6-4.6) in nsq cohort and 2.9 months (95% CI 1.6-6.2) in sq cohort. Median OS was 7.8 months in nsq cohort and 7.9 months in sq cohort. The most frequent grade ≥3 adverse events were anemia (22%), lymphopenia (8%), fatigue (8%) and transaminitis (5%). Conclusions: S1900A failed to show the requisite level of efficacy for rucaparib in advanced NSCLC pts with high genomic LOH and/or a BRCA1/2 mutation. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Genomic LOH as a phenotypic marker of HRD does not predict sufficient activity of rucaparib in NSCLC. These results stand in contrast to the high level of efficacy of PARPi in patients with BRCA-associated or high LOH cancers of other tumor types. Underlying biologic differences in the genomic characteristics of these cancers vs. NSCLC may be responsible. Studies examining this premise are ongoing. (NCT03845296). Clinical trial information: NCT03845296.

Efficacy and safety of anti-PD-1-based therapy in combination with PARP inhibitors for patients with advanced solid tumors in a real-world setting

BackgroundRationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited.MethodEfficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).ResultsThis retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events.ConclusionPARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.

Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors.

Testicular germ cell tumors (TGCTs) are the most common cancers in men aged 15–39 years and are divided into two major groups, seminomas and nonseminomas. Novel treatment options are required for these patients, to limit side effects of chemotherapy. We hypothesized that promoter methylation of relevant homologous recombination (HR) genes might be predictive of response to poly‐ADP ribose polymerase inhibitors (PARPis) in TGCTs. We report a study pipeline combining in silico, in vitro, and clinical steps. By using several databases and in silico tools, we identified BRCA1, RAD51C, PALB2, RAD54B, and SYCP3 as the most relevant genes for further investigation and pinpointed specific CpG sites with pronounced negative correlation to gene expression. Nonseminomas displayed significantly higher methylation levels for all target genes, where increased methylation was observed in patients with more differentiated subtypes and higher disease burden. We independently performed second‐line targeted validation in tissue series from TGCT patients. A moderate and/or strong anti‐correlation between gene expression (assessed by RNA‐sequencing) and promoter methylation (assessed by 450k array) was found, for all of the targets. As a proof of concept, we demonstrated the sensitivity of TGCT cell lines to Olaparib, which associated with differential methylation levels of a subset of targets, namely BRCA1 and RAD51C. Our findings support the use of HR genes promoter methylation as a predictor of the therapeutic response to PARPis in patients with TGCT.

Abstract PS10-47: Physician and patient satisfaction with poly(ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy in adult patients with germline BRCA1/2 mutated (gBRCA1/2mut) HER2- advanced breast cancer (ABC): Results from a multi-country real-world (RW) study

Abstract Background: Within the past 3 years, PARPi have demonstrated improved progression-free survival and favorable PROs compared with chemotherapy in randomized clinical trials in patients with gBRCA1/2mut HER2- ABC. These agents are now available in multiple countries for the treatment of gBRCA1/2mut HER2- locally advanced and/or metastatic breast cancer. Limited information is available on physician/patient satisfaction with PARPi from the RW. We assessed RW physician/patient treatment satisfaction among adult patients with gBRCA1/2mut HER2- ABC in Germany, France, Italy, Spain (EU4), US, and Israel. Methods: Oncologist were recruited to abstract data from medical records (2019/2020) for patients with gBRCA1/2mut HER2- ABC. Physicians were asked to rank (1=very dissatisfied to 5=very satisfied) their satisfaction with their patient’s current ABC treatment. The scores were dichotomized to a 0/1 variable (0=very dissatisfied/ dissatisfied/moderately satisfied; 1=satisfied/very satisfied). A subset of patients completed the Cancer Treatment Satisfaction Questionnaire, a validated instrument that was used to measure patient’s satisfaction with their current therapy. The physician and patient sample were matched. Physician/patient satisfaction scores were compared between chemotherapy and PARPi monotherapy utilizing inverse probability weighted regression adjustment controlling for age at therapy initiation, Charlson Comorbidity Index at time of data collection, baseline symptoms, hormone receptor (HR) status, ECOG score at therapy initiation, stage of therapy initiation (locally advanced breast cancer or metastatic breast cancer) and number of lines of ABC treatment. Results: Overall 96 adult female patients participated; mean age was 51 years. Tumor characteristics were: 34.4% HR+/HER2-, 65.6% triple negative breast cancer. Chemotherapy (n=58) was received among 60.4% of pts [n=29 (50.0%) platinum based, n=29 (50.0%) non-platinum based], and PARPi monotherapy (n=38) was received among 39.6% of pts. Physicians were significantly more likely to be satisfied or very satisfied with PARPi in comparison with chemotherapy (95.4% vs. 40.8%, p<0.001). Mean patient satisfactions scores were numerically higher with PARPi vs. chemotherapy: expectation of therapy 81.3 vs. 72.0 (p=0.13), feelings about side effects 55.7 vs. 51.4 (p=0.30), satisfaction with therapy 74.0 vs. 68.5 (p=0.13). Conclusions: PARPi have demonstrated superior efficacy and favorable PROs vs. chemotherapy in randomized controlled trials. In this RW study, physicians reported significantly higher satisfaction with PARPi vs. chemotherapy; patients reported numerically higher satisfaction scores with PARPi vs. chemotherapy across all domains. These findings further support the value of PARPi in patients with gBRCA1/2mut HER2- ABC. Additional studies to validate these findings are planned. Funding: Pfizer Citation Format: Michael Patrick Lux, Alexander Niyazov, Katie Lewis, James Pike, Alex Rider, Bhakti Arondekar, Reshma Mahtani. Physician and patient satisfaction with poly(ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy in adult patients with germline BRCA1/2 mutated (gBRCA1/2mut) HER2- advanced breast cancer (ABC): Results from a multi-country real-world (RW) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-47.

Abstract PS10-11: Associations with response to poly(ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA mutated metastatic breast cancer: Results of a meta-regression analysis

Abstract Background: PARP inhibitors (PARPi), when given as single agents, have modest antitumor activity in patients with advanced breast cancer and mutation in BRCA1 or BRCA2. It is unclear whether some subgroups derive greater benefit from treatment.Methods: Two electronic databases (MEDLINE, CENTRAL) and one registry (Clinicaltrials.gov) were searched from inception to June 2020 to identify trials of PARPi in patients with metastatic breast cancer. Objective response rate (ORR) and disease control rate (DCR) to PARPi were extracted and pooled in a meta-analysis using the Mantel Haenszel random effects model. Analyses were performed for patients with a BRCA mutation exclusively. Meta-regression explored the influence of patient and tumor characteristics and previous chemotherapy on ORR and DCR as reported in individual studies. Analysis comprised of a linear regression weighted by individual study sample size using the weighted least squares (mixed effect) method. Quantitative significance was defined using methods described by Burnand et al. Results: Twenty-two studies comprising 1627 patients were identified and among these 1466 (90%) patients had a germline (n=1451) or a somatic (n=15) BRCA mutation and were included in the analysis. In 7 of these studies (32%; n=680 patients), the PARPi was given in combination with a platinum-based chemotherapy.; 54% of breast cancers were triple-negative. 81% of patients had received at least 1 prior line of chemotherapy in the metastatic setting and 28% were previously exposed to a platinum-based chemotherapy in the metastatic setting. Pooled ORR was 46%; 66% when combined with platinum vs 36% with PARPi alone (OR 3.44, 2.77-4.29, p0.001). Meta-regression results are shown in the Table. Previous chemotherapy in the metastatic setting, especially platinum-based chemotherapy, was associated with highly significantly lower ORR as defined by by Burnand et al. Age and hormone receptor status were not associated with response. Quantitatively similar results were observed for DCR. Conclusion: PARPi therapy is associated with lesser response in patients with prior chemotherapy exposure, especially platinum-based treatment. There was no association between ORR and hormone receptor status or age. Dependent variableVariableCoefficients BêtaSignifianceORR BRCA1/2n = 146645.67 %Age-0.320.34Previous chemotherapy in metastatic setting-0.700.004Previous platinum in metastatic setting-0.620.02Platinum refractory-0.390.22Hormone receptor positive0.190.48Triple negative-0.120.66DCR BRCA1/2n = 126071.47 %Age-0.240.53Previous chemotherapy in metastatic setting-0.740.006Previous platinum-0.420.21Platinum refractory-0.070.83Hormone receptor positive-0.120.69Triple negative0.230.47 Citation Format: Alexandra Desnoyers, Brooke E. Wilson, Michelle B. Nadler, Eitan Amir. Associations with response to poly(ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA mutated metastatic breast cancer: Results of a meta-regression analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-11.

Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer.

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.

Abstract PS10-53: Treatment Patterns and Clinical Outcomes Among Patients with germline BRCA1/2 mutated (gBRCA1/2mut) HER2+ Advanced Breast Cancer (ABC): Results from a US Real-world Study

Abstract Background: gBRCA1/2mut ABC represents ~5% of all breast cancer (BC), although a fair estimate of gBRCA1/2mut HER2+ BC remains to be determined. HER2-targeted therapy is the current standard of care for these patients with HER2+ BC. While PARP inhibitors (PARPi) are approved for the treatment of gBRCA1/2mut HER2- ABC, recently, NCCN updated its guidelines (v6.2020) to additionally consider the use of PARPi in patients with gBRCA1/2mut HER2+ metastatic BC. However, clinical trials have not evaluated the efficacy of PARPi among patients with gBRCA1/2mut HER2+ metastatic BC. In order to establish a baseline reference point, we assessed real-world treatment patterns and clinical outcomes among patients with gBRCA1/2mut HER2+ ABC. Methods: US Oncologists retrospectively reviewed charts (July 2019-June 2020) of randomly selected patients ≥18 y, with gBRCA1/2mut ABC who received ≥1 cytotoxic chemotherapy (CT) regimen(s) for ABC between Jan 2013-April 2018. A descriptive analysis was performed for the HER2+ patients including 1st line ABC treatment patterns. Clinical outcomes (1st line ABC PFS rates) were estimated using the Kaplan-Meier method. PARPi clinical outcomes data were immature given its recent launch. Additional analyses evaluating outcomes in patients receiving PARPi are planned. Results: Of the 387 patients with gBRCA1/2mut ABC included in the study, 82 (21%) female patients had HER2+ disease. Of the gBRCA1/2mut HER2+ patients, median age was 56y, 72% were white. Clinical characteristics: 62% HR+/HER2+, 37% HR-/HER2+, and 1% had unknown HR/HER2+ ABC. Treatments in the 1st line setting for HR+/HER2+ ABC patients (n=51) included CT (55%) and CT + HER2-targeted therapy (43%). First-line treatments used for HR-/HER2+ ABC patients (n=30) included CT + HER2-targeted therapy (77%) and CT (20%). 12-month PFS rate for 1st line HR+/HER2+ patients was 77% and for HR-/HER2+ patients was 64%. Later line treatments will be presented. Conclusion: In this analysis of HER2+ patients with gBRCA1/2mut ABC, unexpectedly low rates of HER2-targeted therapy were observed in patients with HR+/HER2+ disease. Appropriately high rates of HER2-targeted therapy with CT was observed among gBRCA1/2mut HR-/HER2+ patients. Treatment patterns among patients with non-gBRCA1/2mut HER2+ ABC in a real-world setting need to be evaluated. Clinical outcome findings from this study demonstrate the need to better understand best treatment strategies for this patient population. As PARPi are not yet approved for patients with gBRCA1/2mut HER2+ ABC, studies assessing efficacy of PARPi +/- HER2-targeted therapy are warranted. Funding: Pfizer Citation Format: Elias Obeid, Rohan C Parikh, Elizabeth Esterberg, Bhakti Arondekar, Abigail Hitchens, Lillian Shahied Arruda, Alexander Niyazov. Treatment Patterns and Clinical Outcomes Among Patients with germline BRCA1/2 mutated (gBRCA1/2mut) HER2+ Advanced Breast Cancer (ABC): Results from a US Real-world Study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-53.

The role of PARP inhibitors in BRCA mutated pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence relative to other solid tumors, it is one of the leading causes of cancer-related death in the US. PDAC is highly resistant to chemotherapy as well as radiation therapy. Current standard-of-care chemotherapeutic regimens provide transient disease control but eventually tumors develop chemoresistance. Tumors that are deficient in DNA damage repair mechanisms such as BRCA mutants respond better to platinum-based chemotherapies. However, these tumor cells can utilize the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) as a salvage DNA repair pathway to prolong survival. Hence, in the presence of BRCA mutations, the inhibition of the PARP pathway can lead to tumor cell death. This provides the rationale for using PARP inhibitors in patients with BRCA mutated PDAC. The phase III POLO trial showed a near doubling of progression-free survival (PFS) compared with placebo in advanced PDAC when a PARP inhibitor, olaparib, was used as maintenance therapy. As a result, the US Food and Drug Administration (FDA) approved olaparib as a maintenance treatment for germline BRCA mutated advanced PDAC that has not progressed on platinum-based chemotherapy. The success of olaparib in treating advanced PDAC opened the new field for utilizing PARP inhibitors in patients with DNA damage repair (DDR) gene defects. Currently, many clinical trials with various PARP inhibitors are ongoing either as monotherapy or in combination with other agents. In addition to germline/somatic BRCA mutations, some trials are enrolling patients with defects in other DDR genes such as ATM, PALB2, and CHEK2. With many ongoing PARP inhibitor trials, it is hopeful that the management of PDAC will continuously evolve and eventually lead to improved patient outcomes.

Efficacy and safety of PARP inhibitors in the treatment of advanced ovarian cancer: An updated systematic review and meta-analysis of randomized controlled trials.

Poly-ADP-ribose polymerase (PARP) inhibitors have emerged as a novel class of therapeutics for ovarian cancer (OC); however, PARP inhibitors present a class effect adverse-event profile. A comprehensive literature review was performed for phase II or III randomized controlled trials (RCTs) published up to and including January 2020. We analyzed relevant clinical trials reporting the efficacy and toxicity profile of PARP inhibitors in patients with advanced OC. We estimated hazard ratios (HRs), incidences, risk ratios (RRs) and relative 95 % confidence intervals (95 % CI) for progression-free survival (PFS) and selected adverse events, using Stata 12.0 software package. The systematic review process yielded 10 eligible trials comprising 4,241 patients with advanced OC for survival analysis and 4553 patients for evaluation of toxicity profile. The pooled HR (PARP inhibitor vs control group) for PFS was 0.41 (95 % CI, 0.35-0.50) in overall patients, 0.51 (95 % CI, 0.40-0.64) in unselected setting, 0.32 (95 % CI, 0.26-0.39) in BRCA mutation setting, and 0.57 (95 % CI, 0.41-0.78) in wild-type setting. Patients treated with PARP inhibitors exhibited higher risks of all-grade and high-grade haematological toxicities, including anemia, leucopenia, neutropenia, thrombocytopenia (P < 0.05), and also presented higher risks of all-grade gastrointestinal side effects, including constipation, diarrhea, nausea, and vomiting as well as high-grade nausea and vomiting (P < 0.05). This study indicated that the use of PARP inhibitor provided substantial progression-free survival (PFS) benefits, irrespective of BRCA mutation status; however, treatment with PARP inhibitor was associated with increased risks of selected treatment-related adverse events.

A survey on improving validation in plasma samples by niraparib and LC-MS/MS methods

The objective of an exit survey is to improve and authorize a rapid and efficient “liquid chromatography-tandem mass spectrometry (LC-MS/MS)” technique for examination of Niraparib in plasma samples. Niraparib was separated utilizing “X-Bridge C18, 50 x 4.6 mm”, 5 µm column with MP composed of 10 mM Methanol &amp;Ammonium format in a proportion of (20:80 v/v). MRM positive mode is utilized to identify the Niraparib at 321.5®195.4. The approach illustrates sinter &amp;intra- day precision surrounded by0.7 to 2.0 and 0.7 to 2.7 % and accuracy within 101.4-102.4 &amp; 99.5-104.8 %. Germline mutations in BRCA1 and 2, two genes associated with mechanisms of DNA reparation impairment, are appeared to be connected with breast incidence and malignant ovarian growth, both irregular&amp; familiar. PARP is a group of enzymes engaged with BER system. The presentation of PARP inhibitors in patients with BRCA-transformed ovarian malignant growth is associated with the synthetic lethality concept. Niraparib (NR) is an inhibitor of "poly (ADP-ribose) polymerase (PARP) enzymes", PARP-1, and PARP-2 performs a character in DNA restoration. We observed such vast numbers of challenges with the revealed strategies regarding stability &amp;reproducibility for long-run analysis. It is crucial to building up the tremendous bioanalytical method with appropriate Deuterated or analog-based internal standard in terms of reproducibility and matrix effect.

Prevalence of hereditary breast and ovarian cancer predisposition gene mutations among 882 HBOC high-risk Chinese individuals

Objective: Identification of deleterious variants in HBOC susceptible genes allows for increased clinical surveillance and early detection, and could predict the response to PARP inhibitor in patients with advanced ovarian carcinomas.

Prevalence and Spectrum of BRCA Germline Variants in Central Italian High Risk or Familial Breast/Ovarian Cancer Patients: A Monocentric Study.

Hereditary breast and ovarian cancers are mainly linked to variants in BRCA1/2 genes. Recently, data has shown that identification of BRCA variants has an immediate impact not only in cancer prevention but also in targeted therapeutic approaches. This prospective observational study characterized the overall germline BRCA variant and variant of uncertain significance (VUS) frequency and spectrum in individuals affected by breast (BC) or ovarian cancer (OC) and in healthy individuals at risk by sequencing the entire BRCA genes. Of the 363 probands analyzed, 50 (13.8%) were BRCA1/2 mutated, 28 (7.7%) at BRCA1 and 23 (6.3%) at BRCA2 gene. The variant c.5266dupC p.(Gln1756Profs) was the most frequent alteration, representing 21.4% of the BRCA1 variants and 12.0% of all variants identified. The variant c.6313delA p.(Ile2105Tyrfs) of BRCA2 was the most frequent alteration observed in 6 patients. Interestingly, two new variants were identified in BRCA2. In addition, 25 different VUS were identified; two were reported for the first time in BRCA1 and two in BRCA2. The number of triple-negative BCs was significantly higher in patients with the pathogenic BRCA1/2-variant (36.4%) than in BRCA1/2 VUS (16.0%) and BRCA1/2 wild-type patients (10.7%) (p < 0.001). Our study reveals that the overall frequency of BRCA germline variants in the selected high-risk Italian population is about 13.8%. We believe that our results could have significant implications for preventive strategies for unaffected BRCA-carriers and effective targeted treatments such as PARP inhibitors for patients with BC or OC.

Efficacy of PARP inhibitors in patients with cancer: a meta-analysis of randomized trials

Efficacy of PARP inhibitors in patients with cancer: a meta-analysis of randomized trials

Recent Developments in the Management of Advanced Prostate Cancer

Numerous new options are available for the treatment of prostate cancer when it progresses beyond localized disease. Older drugs, first developed for treatment of metastatic castration-resistant prostate cancer (CRPC), are being used to treat nonmetastatic disease based on results of large randomized controlled trials. Sequencing of available treatment options is challenging for CRPC, but there is some guidance from trial data. Cross-resistance among newer hormonal drugs is a concern, and therefore switching to another class of drug is preferred. Emerging treatments on the horizon, such as PARP inhibitors in patients with BRCA2 mutations and lutetium-177 in those with prostate-specific membrane antigen (PSMA)–positive disease, may look promising to improve outcomes among those with advanced prostate cancer.

Practice-Changing Interventions in the Systemic Management of Breast Cancer

Systemic treatment for metastatic breast cancer now incorporates many targeted agents and a plethora of combinations specific to the breast cancer subtype. New to the treatment paradigm are fam-trastuzumab deruxtecan-nxki, and tucatinib for HER2-positive disease; the PI3K inhibitor alpelisib in combination with fulvestrant for estrogen receptor–positive and PIK3CA-mutated tumors; PARP inhibitors for patients with germline BRCA1/2 mutations; and the anti–PD-L1 agent atezolizumab in combination with albumin-bound paclitaxel for triple-negative disease with PD-L1 mutations in tumors. In addition, for estrogen receptor–positive disease, the role of CDK4/6 inhibitors increased substantially during the past year, as overall survival results have emerged. These targeted agents are greatly improving patient outcomes, and thus have all been incorporated into the NCCN Guidelines for Breast Cancer.

Abstract A18: Evaluating the potential to repurpose statins for ovarian cancer therapy

Abstract The recent success of PARP inhibitors in patients with BRCA1/2 mutant ovarian tumors highlights the importance of identifying druggable vulnerabilities in this disease. The fact that not all ovarian cancer patients will benefit from PARP inhibitors or experience durable responses places great emphasis on the need to identify additional therapies. Repurposing existing FDA-approved drugs offers an opportunity to accelerate the progress of drug development. Statins are drugs primarily prescribed for hypercholesterolemia and have been scrutinized for decades. Some studies demonstrated, through epidemiologic approaches and experimental studies, that statins have anticancer properties. We hypothesized that statins can be repositioned as part of a therapeutic regimen for HGSOC. Here, we demonstrate that certain ovarian cancer cell lines are exquisitely sensitive to treatment with statins. In addition, we show that the sensitivity to statins is an on-target effect by rescuing with downstream members of the mevalonate pathway. Our ongoing studies reveal that HGSOC cells that are sensitive to stain treatment manifest an amplification of chromosome 1q21. Within this genomic region are the S100 proteins, previously identified as potential biomarkers in several cancers, as well as the antiapoptotic protein MCL1. Using reverse phase protein arrays (RPPA) we found that MCL1 levels were altered in statin-sensitive cell lines, while there was no such change in non-sensitive lines. After identifying MCL1 as a potential marker of response, Western blot analysis demonstrated a dose-dependent decrease in the protein level of MCL1 with increasing statin concentration. Additionally, a short, proapoptotic splice variant of MCL1 was produced upon statin treatment, but only in the sensitive lines. Mechanistically, we find that phospho-YAP (inactive) is upregulated after statin treatment. Using a syngeneic cell line system, we were able to demonstrate that overexpression of YAP increases sensitivity to statins. Interestingly, a constitutively active form of YAP (nonphosphorylatable) remains insensitive, suggesting the importance of the phosphorylation event itself. This data corroborated previous research that suggested that multiple different statins decrease nuclear YAP and suggest a mechanism for statin sensitivity. Given its role as an oncogene, the apparent ability of statins to deactivate YAP and downregulate MCL1 steers statins in a promising direction for their repositioning for future therapeutic use. Citation Format: Paul T. Kroeger, Jr., Ronny Drapkin. Evaluating the potential to repurpose statins for ovarian cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A18.