Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: Safety analyses from the randomized, placebo-controlled, phase III TALAPRO-2 study.

BACKGROUND: This detailed analysis further characterizes the safety profile of talazoparib plus enzalutamide in the ongoing randomized, phase III TALAPRO-2 study in patients with metastatic castration-resistant prostate cancer (mCRPC). In both the all-comers and homologous recombination repair (HRR)-deficient populations, talazoparib plus enzalutamide significantly improved radiographic progression-free survival compared with placebo plus enzalutamide. METHODS: The talazoparib plus enzalutamide safety populations in TALAPRO-2 included 398 patients from cohort 1 (all-comers, unselected for HRR gene alterations) and 198 patients from the combined HRR-deficient population (patients from the all-comers population with HRR gene alterations plus subsequently enrolled patients with HRR gene alterations; cohort 2). Patients received talazoparib 0.5 mg (0.35 mg, moderate renal impairment) and enzalutamide 160 mg once daily. Safety analyses evaluated common treatment-emergent adverse events (TEAE), their type, severity, timing, seriousness, and relationship to study treatment. RESULTS: In the all-comers (n = 398) and HRR-deficient populations (n = 198), all-cause grade 3/4 (G3/4) TEAEs with talazoparib plus enzalutamide were reported in 71.9 % and 66.2 % of patients, respectively. Most common G3/4 hematologic TEAEs were anemia (46.7 % and 40.9 %, respectively), neutropenia (18.3 % and 18.7 %), and thrombocytopenia (7.3 % and 7.1 %). Median time to event was 3.3 and 3.3 months for G3/4 anemia, 2.3 and 2.3 months for G3/4 neutropenia, and 2.3 and 1.5 months for G3/4 thrombocytopenia. Maximum hemoglobin reduction occurred after 13 and 15 weeks of treatment. 18.8 % and 10.1 % of patients discontinued talazoparib. TEAEs were managed with dose interruption (62.1 % and 57.6 %), reduction (52.8 % and 52.0 %), hematologic supportive care (13.1 % and 10.6 %), and packed red blood cell transfusions (39.2 % and 35.9 %). CONCLUSION: Talazoparib plus enzalutamide had a generally manageable safety profile in patients with mCRPC within the all-comers and the HRR-deficient populations. GOV IDENTIFIER: NCT03395197.

Exploring Molecular Drivers of PARPi Resistance in BRCA1-Deficient Ovarian Cancer: The Role of LY6E and Immunomodulation.

Approximately 50% of patients diagnosed with ovarian cancer harbor tumors with mutations in BRCA1, BRCA2, or other genes involved in homologous recombination repair (HR). The presence of homologous recombination deficiency (HRD) is an approved biomarker for poly-ADP-ribose polymerase inhibitors (PARPis) as a maintenance treatment following a positive response to initial platinum-based chemotherapy. Despite this treatment option, the development of resistance to PARPis is common among recurrent disease patients, leading to a poor prognosis. In this study, we conducted a comprehensive analysis using publicly available datasets to elucidate the molecular mechanisms driving PARPi resistance in BRCA1-deficient ovarian cancer. Our findings reveal a central role for the interferon (IFN) pathway in mediating resistance in the context of BRCA1 deficiency. Through integrative bioinformatics approaches, we identified LY6E, an interferon-stimulated gene, as a key mediator of PARPi resistance, with its expression linked to an immunosuppressive tumor microenvironment (TME) encouraging tumor progression and invasion. LY6E amplification correlates with poor prognosis and increased expression of immune-related gene signatures, which is predictive of immunotherapy response. Interestingly, LY6E expression upon PARPi treatment resistance was found to be dependent on BRCA1 status. Gene expression analysis in the Orien/cBioPortal database revealed an association between LY6E and genes involved in DNA repair, such as Rad21 and PUF60, emphasizing the interplay between DNA repair pathways and immune modulation. Moreover, PUF60, Rad21, and LY6E are located on chromosome 8q24, a locus often amplified and associated with the progression of ovarian cancer. Overall, our study provides novel insights into the molecular determinants of PARPi resistance and highlights LY6E as a promising prognostic biomarker in the management of HRD ovarian cancer. Future studies are needed to fully elucidate the molecular mechanisms underlying the role of LY6E in PARPi resistance.

Prostate Cancer, Pathophysiology and Recent Developments in Management: A Narrative Review.

PURPOSE OF REVIEW: Prostate cancer is the second most common cancer in men. The different stages of prostate cancer which include localised (low, intermediate, and high risk) disease, locally advanced, non-metastatic castration-resistant prostate cancer (M0 CRPCa), and metastatic disease. The main treatment of locally advanced disease is external beam radiotherapy with hormonal therapy which are associated with good prognosis. RECENT FINDINGS: Current treatments for M0 CRPCa include androgen deprivation therapy in combination with apalutamide, darolutamide or enzalutamide, all of which are associated with good metastatic-free survival rates in clinical trials. Hormone-naive metastatic prostate cancer comprises the same treatments as M0 CRPCa, whereas further treatment includes docetaxel and abiraterone. Metastatic castration-resistant prostate cancer treatments include sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, which aim to slow down the progression of the disease and to prolong life. This article also provides insight into the development of new drugs recently approved for metastatic castration prostate cancer, which include PARP inhibitors and Lutetium-177 which have shown to have significantly good overall survival and to improve radiographic progression-free survival. In addition, new clinical trials are ongoing to test new medications such as cabozantinb and chimeric-antigen receptor T-cell therapy for the treatment of advanced prostate cancer. With the aim to slow down the progression of the disease and to prolong life, new drug developments are underway to hopefully provide a positive impact on overall survival and improve progression-free survival, especially in advanced prostate cancer.

Efficacy and safety of rucaparib in patients with recurrent high-grade ovarian carcinoma: A systematic review and meta-analysis.

Ovarian cancer stands as the third most prevalent gynecological malignancy. The advent of PARP inhibitors, particularly rucaparib, has revolutionized the landscape of advanced ovarian cancer treatment, demonstrating notable efficacy with minimal toxicity, especially in patients not previously exposed to PARP inhibitors. Rucaparib's precision-driven approach, targeting specific genetic mutations, disrupts DNA repair mechanisms, resulting in cytotoxic effects on neoplastic cells. This comprehensive review delves into the clinical efficacy and safety profile of rucaparib in recurrent ovarian cancer, showcasing its promising therapeutic approach. A systematic search of studies reporting rucaparib efficacy and safety, up to September 2023, was conducted across various reputable databases and sources. The meta-analysis of seven articles revealed a pooled objective response rate (ORR) of 0.331 (95% CI, 0.221-0.449; I2 = 92.4%), underscoring rucaparib's efficacy, particularly evident in the BRCA-mutated cohort. Rucaparib consistently outperformed controls in progression-free survival (PFS) and overall survival (OS). Safety evaluations indicated that 98.7% of patients experienced treatment-emergent adverse events (TEAEs), with 61% being grade ≥3. Notable TEAEs included nausea (69.0%), fatigue (66.8%), vomiting (37.3%), and constipation (32.1%). Hematological concerns comprised anemia (47.9%), thrombocytopenia, elevated AST/ALT (37.3%), and serum creatinine levels (19.7%). Despite favourable outcomes, the rucaparib group recorded higher event rates across various metrics than controls. The findings underscore the need for meticulous monitoring and dose adjustments to optimize therapeutic outcomes and mitigate the increased risks associated with adverse events. International Prospective Register of Systematic Review Identifier: CRD42023459646.

Efficacy and safety of PARPis combined with an ICIs for advanced or metastatic triple-negative breast cancer: a single-arm meta-analysis.

Although the intervention for triple-negative breast cancer (TNBC) patients has improved and survival time has increased, the combination of immune checkpoint inhibitors(ICIs) and PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors, PARPis) is still controversial. Previous studies revealed that the combined use of ICIs and PARPis led to increased antitumor activity. However, most of these combined regimens are nonrandomized controlled trials with small sample sizes. The purpose of this meta-analysis was to evaluate the efficacy and safety of ICIs combined with PARPis in patients with advanced or metastatic TNBC. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched. The results including the objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs), were subjected to further analysis. Four studies involving 110 subjects were included in this meta-analysis. The combined ORR and DCR were 23.6% and 53.6%, respectively; while the ORR and DCR of BRCAmut patients were 38.1% and 71.4%, respectively. The median PFS of the patients was 4.29 months. As for safety, the most common AEs were nausea (49.0%), anemia (44.3%) and fatigue (40.6%). Most of them were grade 1 or 2, and the incidence of adverse events ≥ III was obviously low. Except for anemia, the incidence of AEs ≥ III was < 10%. This meta-analysis revealed that the combination of ICIs and PARPis has good efficacy and safety for advanced or metastatic TNBC patients.

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). RESULTS: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. CONCLUSION: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.

Clinicopathological and molecular features of tubo-ovarian carcinosarcomas: a series of 51 cases.

Objective: Tubo-ovarian carcinosarcomas are rare, extremely aggressive malignant tumors that contain both carcinomatous and sarcomatous components. Due to the disease's rarity, developing an effective treatment strategy for ovarian carcinosarcomas has been challenging. A study was conducted to investigate the clinicopathologic and molecular features of this rare disease. Methods: We enrolled all patients diagnosed with tubo-ovarian carcinosarcomas from January 2007 to December 2022. The clinical and pathological data were gathered from medical records. Kaplan-Meier curves were plotted to calculate OS and PFS. The Log-rank test and Cox regression model were utilized to explore the relationship between clinicopathological parameters and survival. Patients with cancer tissues available had sequencing with a 242-gene panel done to investigate the mutational landscape and signature of the disease. Results: In total, 65% of the patients were diagnosed with advanced-stage cancer. The median PFS and OS of this cohort were 27 and 40 months, respectively, and there was no significant difference in survival between the homologous and heterologous components of sarcoma. Unexpectedly, staging did not have effects on prognosis. All patients had surgical attempts, and suboptimal debulking status was correlated with poorer PFS and OS. MSI was identified in 0% with low Tumor mutation burden (TMB) indicating a poor response to immunotherapy. Low HER2 expression is controversial, according to previous reports, and gives us limited choices with this rare and aggressive disease. We surprisingly found the homologous recombination deficiency (HRD)-positive status was identified in 64% of OCS, which is significantly higher than UCS and other types of epithelial ovarian cancer. The fact that all patients in our cohort who received olaparib as maintenance therapy had survived over 30 months and two had no evidence of recurrence at the latest follow-up might further validate the role of poly (ADP-ribose) polymerase inhibitors (PARPi) in the management of OCS. Conclusion: OCS patients seemed to respond to carboplatin/paclitaxel with optimal PFS and OS. Cytoreduction with no residuals proved to be the sole independent prognostic factor. WES should be done to assess the prognosis and assist with the targeted therapy, especially the HRD test, which might help select potential patients who benefit from PARPi.

Talazoparib for the treatment of prostate cancer.

INTRODUCTION: Around 25% of patients with advanced prostate cancer harbor alterations in the homologous recombination/DNA damage repair (HRR) pathway. Inhibiting poly (ADP-ribose) polymerase (PARP) in these patients leads to synthetic lethality, making PARP inhibitors (PARPi), including talazoparib, a promising treatment for metastatic castration-resistant prostate cancer (mCRPC) and potentially for metastatic hormone-sensitive prostate cancer (mHSPC). AREAS COVERED: This article examines the mechanism of action, chemical properties, pharmacokinetics, pharmacodynamics, and clinical safety and efficacy data of different PARPis, including talazoparib in prostate cancer. It reviews the TALAPRO-1 and TALAPRO-2 clinical trials and the ongoing TALAPRO-3 trial. EXPERT OPINION: Despite recent therapeutic advancements, mCRPC remains a lethal disease. Androgen receptor pathway inhibitors (ARPIs) are approved for patients with mCRPC and mHSPC, yet most patients first receive these agents in the castration-resistant setting. Real-world data indicate that around half of patients with mCRPC do not receive subsequent lines of therapy, underscoring the efficacy of upfront combination therapies. The combinations of ARPI plus PARPi are indicated for patients with mCRPC harboring HRR mutations, though identifying these patients is challenging due to limited genomic testing. Further research and improved access to genomic testing are essential to optimize treatment strategies.

Past and present: a bibliometric study on the treatment of recurrent ovarian cancer.

Background: Ovarian cancer (OC) is a gynecological malignancy with a high mortality rate worldwide. The unfavorable prognosis of OC is mainly attributed to the recurrent propensity. Recently, mortality from OC has exhibited a downward trend. These favorable patterns are likely to be driven by advancements in novel therapeutic regimens. However, there is a lack of visualize analysis of the application of these new drugs on women with recurrent OC (ROC). Therefore, we aimed to provide a bibliometric analysis of the evolving paradigms in the ROC treatment. Methods: Documents on ROC treatment were systematically collected from the MEDLINE database and Web of Science Core Collection (WOSCC). The retrieved documents were exported in the plain text file format, and files were named and saved to the paths specified by the Java application. Microsoft Excel (version 2010), Citespace (6.2.R4) and VOSviewer (1.6.19) were used for data analysis, and included the following: 1) annual publication trend; 2) contributions of countries, institutions and authors; 3) co-citation of journals and references; and 4) co-occurrence of keywords. Results: A total of 914 documents published in the MEDLINE and 9,980 ones in WOSCC were retrieved. There has been an upward trend in the productivity of publications on ROC treatment on by years. The United States was the leading contributor in this field, and the University of Texas System stood out as the most productive institution. Giovanni Scambia and Maurie Markman were the research leaders in the field of ROC treatment. The journal Gynecologic Oncology had the highest citation frequency. The reference entitled with "Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer" got highest centrality of 0.14 in the co-citation network. Keyword analysis revealed that the focus of current ROC treatment was on platinum-based anticancer drugs, paclitaxel, angiogenesis inhibitors (AIs), immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase inhibitors (PARPis). Conclusion: Scholars from a multitude of countries have been instrumental in the advancement of ROC treatment. The research hotspots and trend in the field of predominantly originated from leading international journals and specialized periodicals focused on gynecologic oncology. Maintenance therapy using AIs or (and) PARPis has emerged as a significant complement to platinum-based chemotherapy for patients with ROC.

Niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer. METHODS: This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival. RESULTS: Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months. CONCLUSION: Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.

Niraparib as maintenance therapy in Japan: a retrospective observational study using a Japanese claims database.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the leading cause of female mortality in gynecologic malignancies, with a rising incidence in Japan. This study aimed to validate the treatment patterns and safety of niraparib as maintenance therapy for EOC following initial chemotherapy in clinical practice in Japan. METHODS: Leveraging claims data between April 2008 and December 2022, this descriptive study comprised EOC-diagnosed patients receiving initial platinum-based chemotherapy, debulking surgery, and niraparib as maintenance therapy. Patient characteristics, prescription status, transfusion details, and laboratory data were assessed and reported as summary statistics and frequencies. RESULTS: Among 291 patients, the median age was 64.0 years and 94.5% received a 200-mg daily dose of niraparib. At week 12, 78.7% (229/291) continued niraparib treatment, 21.3% (62/291) discontinued, and 52.2% (152/291) required treatment interruptions. Of the 62 patients who discontinued treatment, 27 patients initiated subsequent EOC treatment within 12 weeks following niraparib discontinuation. Blood transfusions were needed in 10.3% (30/291), and of 55 patients with available laboratory data, 61.8% (34/55) had decreased platelet count <100,000/µL, 25.5% (14/55) had decreased hemoglobin level <8 g/dL, and 22.7% (5/22) had decreased neutrophil count <1,000/µL, meeting the criteria for treatment interruption. Among those with thrombocytopenia, 88.2% (30/34) were able to either resume or continue treatment. CONCLUSION: Niraparib demonstrated favorable tolerability in Japanese patients with advanced EOC, with effective management of thrombocytopenia through dose adjustments and supportive care, supporting its viability as post-chemotherapy maintenance therapy.

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved as first-line therapies for breast cancer gene (BRCA)-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. They are also effective for new and recurrent ovarian cancers that are BRCA- or homologous recombination deficiency (HRD)-positive. However, data on these mutations and PARPi use in the Middle East are limited. AIM: To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer. METHODS: This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations, and 25 of 65 ovarian cancer patients tested for HRD. These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023. Data were summarized using descriptive statistics and compared using counts and percentages. Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Among the 472 breast cancer patients, 12.1% underwent BRCA testing, and 38.5% of 65 ovarian cancer patients received HRD testing. Pathogenic mutations were found in 25.6% of the tested patients: 26.3% breast cancers had germline BRCA (gBRCA) mutations and 24.0% ovarian cancers showed HRD. Notably, 40.0% of gBRCA-positive breast cancers and 66.0% of HRD-positive ovarian cancers were Middle Eastern and Asian patients, respectively. PARPi treatment was used in 5 (33.3%) gBRCA-positive breast cancer patients as first-line therapy (n = 1; 7-months progression-free), for maintenance (n = 2; > 15-months progression-free), or at later stages due to compliance issues (n = 2). Four patients (66.6%) with HRD-positive ovarian cancer received PARPi and all remained progression-free. CONCLUSION: Lower testing rates but higher BRCA mutations in breast cancer were found. Ethnicity reflected United Arab Emirates demographics, with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency.

Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.

The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis.

BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.

Skin metastasis from ovarian cancer with somatic BRCA1 mutation: A case report and literature review.

Skin metastasis from ovarian cancer is rare, and its prognosis is poor. Effective therapeutic strategies are currently lacking, but the combination of various treatment methods shrink the tumor and relieve symptoms. The present study reports a rare case of advanced ovarian cancer with skin metastases and intestinal wall thickening, along with a BRCA1 DNA repair associated (BRCA1) mutation. After standard first-line treatment and non-standard second-line treatment, the patient developed skin metastases. The patient's skin itching, pain and lesions were completely relieved after administering bevacizumab in combination with paclitaxel and carboplatin. After 4 months, skin metastases recurred along with anal distension during maintenance treatment with oral poly(ADP ribose) polymerase (PARP) inhibitors. The patient was treated again with bevacizumab combined with docetaxel, and the anal distension was significantly relieved. Angiogenesis therapy combined with chemotherapy is effective, but that the disease-free survival time is short, and PARP inhibitor maintenance effect is limited even in cases with a BRCA1 gene mutation.

CA-125 KELIM as an Alternative Predictive Tool to Identify Which Patients Can Benefit from PARPi in High-Grade Serous Advanced Ovarian Cancer: A Retrospective Pilot Diagnostic Accuracy Study.

BRCA mutation and homologous recombination deficiency (HRD) are the criteria for the administration of PARP inhibitor (PARPi) maintenance therapy. It is known that PARPi efficacy is related to platinum sensitivity and that the latter can be demonstrated from the CA-125 elimination rate constant (KELIM). This study aims to investigate if KELIM can be another tool in the identification of patients that could be benefit from PARPi therapy. Retrospective analysis of patients with high-grade serous advanced ovarian cancer that underwent cytoreduction and was further tested for HRD status. The HRD status was tested either by myChoice HRD CDx assay or by RediScore assay. KELIM score was measured in both neoadjuvant and adjuvant settings with the online tool biomarker-kinetics.org. A total of 39 patients had available data for estimating both HRD status and KELIM score. When assuming KELIM as a binary index test with the value 1 as the cut-off point, the sensitivity was 0.86, 95% CI (0.64-0.97) and the specificity was 0.83, 95% CI (0.59-0.96). On the other hand, when assuming KELIM as a continuous index test, the area under the curve (AUC) was 81% and the optimal threshold, using the Youden index, was identified as 1.03 with a sensitivity of 85.7% and a specificity of 83.3%. KELIM score seems to be a new, cheaper, and faster tool to identify patients that can benefit from PARPi maintenance therapy.

Body composition and inflammation variables as the potential prognostic factors in epithelial ovarian cancer treated with Olaparib.

Background: Epithelial ovarian cancer (EOC) is a significant cause of mortality among gynecological cancers. While Olaparib, a PARP inhibitor, has demonstrated efficacy in EOC maintenance therapy, individual responses vary. This study aims to assess the prognostic significance of body composition and systemic inflammation markers in EOC patients undergoing initial Olaparib treatment. Methods: A retrospective analysis was conducted on 133 EOC patients initiating Olaparib therapy. Progression-free survival (PFS) was assessed through Kaplan-Meier analysis and Cox proportional hazards regression. Pre-treatment computed tomography images were utilized to evaluate body composition parameters including subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), skeletal muscle area index (SMI), and body mineral density (BMD). Inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), serum albumin, and hemoglobin levels, were also measured. Results: The median follow-up duration was 16 months (range: 5-49 months). Survival analysis indicated that high SATI, high VATI, high SMI, high BMD, low NLR, and low PLR were associated with decreased risk of disease progression (all p < 0.05). Multivariate analysis identified several factors independently associated with poor PFS, including second or further lines of therapy (HR = 2.16; 95% CI = 1.09-4.27, p = 0.027), low VATI (HR = 3.79; 95% CI = 1.48-9.70, p = 0.005), low SMI (HR = 2.52; 95% CI = 1.11-5.72, p = 0.027), low BMD (HR = 2.36; 95% CI = 1.22-4.54, p = 0.010), and high NLR (HR = 0.31; 95% CI = 0.14-0.69, p = 0.004). Subgroup analysis in serous adenocarcinoma patients revealed distinct prognostic capabilities of SATI, VATI, SMI, PLR, and NLR. Conclusion: Body composition and inflammation variables hold promise as predictors of therapeutic response to Olaparib in EOC patients. Understanding their prognostic significance could facilitate tailored treatment strategies, potentially improving patient outcomes.

Olaparib with or without bevacizumab versus bevacizumab plus a fluoropyrimidine as maintenance therapy in advanced colorectal cancer: The randomized phase 3 LYNK-003 study.

BACKGROUND: The randomized, open-label, phase III LYNK-003 study assessed the efficacy of first-line maintenance olaparib, alone or in combination with bevacizumab, versus bevacizumab plus a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer (mCRC). We present results of the prespecified interim futility analysis. METHODS: Eligible participants were ≥18 years of age with unresectable or mCRC that had not progressed after induction with first-line bevacizumab plus 5-fluorouracil plus oxaliplatin plus leucovorin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX). Participants were randomly assigned 1:1:1 to olaparib plus bevacizumab, olaparib alone, or bevacizumab plus a fluoropyrimidine (5-fluorouracil or capecitabine). The primary end point was progression-free survival (PFS) per RECIST v1.1 by central review. RESULTS: Between August 2020 and May 2022, 309 participants were assigned to olaparib plus bevacizumab (n = 104), olaparib (n = 107), or bevacizumab plus fluoropyrimidine (n = 98). At interim analysis, with a median follow-up of 7.6 months (range 0.1-19.7 months), the median PFS was 3.7 months (95% CI 2.8-5.3) with olaparib plus bevacizumab (HR 1.52; 95% CI 1.02-2.27; P = 0.982) and 3.5 months (95% CI 2.0-3.7) with olaparib (HR 2.11; 95% CI 1.39-3.18; P = 0.999) versus 5.6 months (95% CI 3.8-5.9) with bevacizumab plus fluoropyrimidine. Treatment-related adverse events occurred in 64 (62%), 52 (50%), and 57 (59%) participants, respectively. There were no treatment-related deaths. CONCLUSION: The LYNK-003 study was stopped prematurely as criteria for futility were met. Maintenance olaparib with or without bevacizumab did not demonstrate clinical efficacy compared with bevacizumab plus a fluoropyrimidine. GOV REGISTRATION: NCT04456699.

Beyond monotherapy: An era ushering in combinations of PARP inhibitors with immune checkpoint inhibitors for solid tumors.

The introduction of PARP inhibitors (PARPis) and immune checkpoint inhibitors (ICIs) has marked a significant shift in the treatment landscape for solid tumors. Emerging preclinical evidence and initial clinical trials have indicated that the synergistic application of PARPis and ICIs may enhance treatment efficacy and potentially improve long-term patient outcomes. Nonetheless, how to identify specific tumor types and molecular subgroups most likely to benefit from this combination remains an area of ongoing research. This review thoroughly examines current studies on the co-administration of PARPis and ICIs across various solid tumors. It explores the underlying mechanisms of action, evaluates clinical efficacy, identifies potential responder populations, and delineates common adverse events alongside strategic management approaches. The aim is to offer a detailed understanding of this combination therapy, potentially guiding future therapeutic strategies for solid tumors.