Targeted Oncology

Concordance Analysis of Microsatellite Instability via NGS and Mismatch Repair Deficiency via IHC in Endometrial and Colorectal Cancer

Assessment of mismatch repair (MMR) function provides critical guidance for diagnosis, prognosis, and therapeutic decision making in colorectal and endometrial cancers. Mismatch repair immunohistochemistry (IHC) is the routine clinical test for identifying MMR deficiency, while microsatellite instability (MSI) serves as its surrogate, detected by polymerase chain reaction or next-generation sequencing (NGS). Available data indicate a high concordance rate between these approaches in colon cancer, whereas a lower concordance has been reported in endometrial cancer. We aimed to assess the concordance rate between MMR-IHC and MSI-NGS from patients with colorectal or endometrial cancer, using IHC as the gold standard. A cohort of 520 patients (352 with endometrial cancer and 168 with colorectal cancer) were included. MMR‑IHC assessed MLH1, MSH2, MSH6, and PMS2 expression, while MSI‑NGS was determined by profiling 130 homopolymer repeat loci using the TruSight Oncology 500 panel from Illumina. While concordance was high in the colorectal cancer cohort (99%, 95% confidence interval 96-100), a lower level of agreement was observed in endometrial cancer cases (85%, 95% confidence interval 81-89). Fifty-two of 53 discordant cases exhibited MMR deficiency by IHC in the absence of detectable MSI. Forty percent of discordant cases could be explained by factors previously associated with reduced MSI levels, including mutations in DNA polymerase genes (n = 5), isolated MSH6 loss (n = 10), atypical IHC staining patterns (n = 8), and germline variants (n = 6). Additionally, the presence of genetic and epigenetic alterations (specifically, 19 cases with MLH1 promoter hypermethylation and ten with somatic or germline MMR variants) supports the interpretation that MSI calls were missed in a subset of cases. Finally, optimizing the MSI threshold enhanced detection accuracy in endometrial tumors. These findings confirm the lower concordance between MMR-IHC and MSI-NGS in endometrial cancer compared with colorectal cancer when broad panels are used, underscoring the importance of tumor-specific interpretation even within tumor-agnostic assays. Although cut-off optimization improved agreement, the evidence remains insufficient for clinical implementation, and further validation studies are needed.

Olaparib: A Review as First-Line Maintenance Therapy in Advanced Ovarian Cancer

Olaparib (Lynparza

Cetuximab in Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Ovarian Cancer Without KRAS, NRAS, or BRAF Mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. NCT02693535 (26 February, 2016).

Comparison of Adverse Events Between PARP Inhibitors in Patients with Epithelial Ovarian Cancer: A Nationwide Propensity Score Matched Cohort Study

Despite improvement in progression-free survival (PFS) with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) as maintenance treatment for patients with epithelial ovarian cancer (EOC), a comparative analysis of clinical events of interest (CEIs) of different PARPi is scarce. This study aimed to compare the safety of different PARPi in patients with EOC. Through analyzing the Korean National Health Insurance Service from January 2009 to January 2022, this study involved BRCA-mutated, platinum-sensitive patients with EOC treated with olaparib (tablet), niraparib, and olaparib (capsule) as first-line or second-line maintenance treatment. CEIs were identified using International Statistical Classification of Diseases (ICD) 9/10 codes, with additional outcomes being dose modification and persistence. In the first-line maintenance treatment [118 niraparib, 104 olaparib (tablet) patients], no significant differences were noted in CEIs, dose reduction, or 6-month discontinuation rate. For second-line maintenance treatment [303 niraparib, 126 olaparib (tablet), and 675 olaparib (capsule) patients], niraparib was associated with a higher risk of hematologic CEIs, particularly anemia, compared with olaparib (tablet) (0.51 [0.26-0.98] and 0.09 [0.01-0.74], respectively), and higher rate of discontinuation rate at 6 months. Of note, patients over 60 years old showed an increased risk of CEIs with niraparib, as indicated by the hazard ratio divergence in restricted cubic spline plots. No differences were observed among the PARPi during first-line maintenance treatment. However, in the second-line maintenance treatment, significant differences were observed in the risk of experiencing CEIs, dose alteration possibilities, and discontinuation of PARPi between niraparib and olaparib (tablets). Moreover, our findings suggest that an age of 60 years may be a critical factor in selecting PARPi to reduce CEI incidence.

Author’s Reply to Jia et al.: “BRCA1 Expression by Immunohistochemistry and Prognosis in Ovarian Cancer: A Systematic Review and Meta‑Analysis”

Comment on: BRCA1 Expression by Immunohistochemistry and Prognosis in Ovarian Cancer: A Systematic Review and Meta‑Analysis

PARP Inhibitors in Ovarian Cancer: A Review

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive overview of data for the PARPis olaparib, niraparib, and rucaparib in patients with OC and discusses their role in disease management, with a focus on the use of PARPis as maintenance therapy in the United States (US). Olaparib was the first PARPi to be approved as first-line maintenance monotherapy in the US, with maintenance niraparib subsequently approved in the first-line setting. Data also support the efficacy of rucaparib as first-line maintenance monotherapy. PARPi maintenance combination therapy (olaparib plus bevacizumab) also provides benefit in patients with newly diagnosed advanced OC whose tumors tested positive for homologous recombination deficiency (HRD). Biomarker testing is critical in the newly diagnosed setting to identify patients most likely to benefit from PARPi maintenance therapy and guide treatment decisions. Clinical trial data support the use of PARPis (olaparib, niraparib, rucaparib) as second-line or later maintenance therapy in patients with platinum-sensitive relapsed OC. Although distinct differences in tolerability profile were observed between PARPis, they were generally well tolerated, with the majority of adverse events managed by dose modification. PARPis had no detrimental effect on patients' health-related quality of life. Real-world data support the use of PARPis in OC, although some differences between PARPis are apparent. Data from trials investigating novel combination strategies, such as PARPis plus immune checkpoint inhibitors, are awaited with interest; the optimal sequencing of novel therapies in OC remains to be established.

Niraparib Maintenance Therapy in Patients with Platinum-Sensitive Recurrent Ovarian Cancer: Real-World Experience at Hospitals in Spain

The reported benefit of poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance in patients with newly diagnosed and platinum (Pt)-sensitive recurrent ovarian cancer (OC) included in randomized clinical trials needs to be corroborated in a less selected population. The aim is to increase the evidence on niraparib in a real-world setting. This is a retrospective observational study including women with platinum-sensitive relapsed high-grade serous OC who started niraparib maintenance between August 2019 (marketing data, Spain) and May 2022. Patients received ≥ 2 previous lines of therapy with complete or partial response to prior chemotherapy. Patient characteristics, niraparib dose, adequacy of dose individualization, effectiveness (progression-free survival [PFS] and overall survival), safety, and economic savings with an individualized starting dose (ISD) strategy were assessed. The study included 217 patients with a median of 8.9 months of niraparib duration: breast cancer gene (BRCA) wild-type OC, 70%; two prior treatment lines, 49%; Research on Adverse Drug Events and Reports (RADAR) criteria, 82% (receiving mainly 200 mg of niraparib, 79%). Median PFS was 10.8 months (95% confidence interval [CI], 8.4-14.8) without statistically significant differences based on starting dose strategy, contrary to what was observed on the basis of prior lines, response to prior chemotherapy, BRCA mutational status, and International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis. The last three variables also showed a statistically significant predictive prognostic value for effectiveness. Dose interruptions due to toxicity were required in 7% of patients, and dose adjustments in 56% were mainly due to hematologic toxicities. The actual dose of niraparib reveals economic savings versus the theoretical cost. This large real-world analysis corroborates the tolerability and activity of niraparib maintenance for platinum-sensitive recurrent OC and economic savings.

Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile

Targeted agents, such as antiangiogenic drugs (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., rucaparib), have been shown to improve outcomes in patients with newly diagnosed or recurrent ovarian cancer. Evidence suggests that combinations of these two classes of targeted agents may result in synergistic antitumor activity. The phase I portion of MITO 25 was designed to determine the maximum tolerated dose, pharmacokinetics, and the safety profile of rucaparib when administered in combination with bevacizumab as maintenance treatment for patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. This was a single-arm, phase I dose-escalation study. Cohorts of three patients were recruited to receive increasing rucaparib doses of 400 mg, 500 mg, or 600 mg twice daily for 28 days. Bevacizumab 15 mg/kg was administered at day 1 every 21 days. We enrolled nine patients. Two patients in the rucaparib 600-mg group had four grade 3 treatment-emergent adverse events: increased in alanine aminotransferase and aspartate aminotransferase levels, depression, and hallucinations. These were deemed to be dose-limiting toxicities related to rucaparib. Because these dose-limiting toxicities occurred in the 600-mg group and affected more than one in three patients, the maximum tolerated dose for rucaparib was considered 500 mg twice daily when combined with bevacizumab 15 mg/kg at day 1 every 21 days. There were no new safety concerns from using the combination. No substantial difference in pharmacokinetic parameters was found between the cohorts or in the pharmacokinetic profiles of rucaparib administered alone or with bevacizumab with respect to historical controls. The maximum tolerated dose of rucaparib is 500 mg twice daily when co-administered with bevacizumab. The plasma concentration-time profiles of rucaparib in combination with bevacizumab suggest no pharmacokinetic interactions between the drugs. The randomized phase II portion of MITO 25 will further investigate rucaparib maintenance treatment with or without bevacizumab in patients with newly diagnosed stage III-IV ovarian cancer who responded to carboplatin-paclitaxel chemotherapy with or without bevacizumab. ClinicalTrials.gov identifier NCT03462212; registered March 2018.

Management of Adverse Events During Rucaparib Treatment for Relapsed Ovarian Cancer: A Review of Published Studies and Practical Guidance

The poly(ADP-ribose) polymerase inhibitor rucaparib is approved as monotherapy in the treatment and maintenance settings for women with relapsed ovarian cancer in the European Union and the United States. We review the safety profile of rucaparib in both settings and provide recommendations for the clinical management of the main adverse events (AEs) that may occur during rucaparib treatment. We searched PubMed and congress proceedings for safety data on oral rucaparib monotherapy (600 mg twice daily) from clinical trials involving patients with relapsed ovarian cancer. AE management guidance was developed from clinical trial protocols, rucaparib prescribing information, oncology association guidelines, and author experience. The most frequent any-grade treatment-emergent AEs (TEAEs) included gastrointestinal symptoms, asthenia/fatigue, dysgeusia, anemia/decreased hemoglobin, and increased alanine/aspartate aminotransferase. Across clinical trials, 61.8% of patients had one or more grade 3 or higher TEAEs. Clinicians should employ close follow-up for TEAEs, particularly early in treatment, and educate patients about expected TEAEs and methods for their monitoring and management (e.g., antiemetics for nausea/vomiting, transfusions for hematologic TEAEs, or dose interruptions/reductions for moderate/severe TEAEs). Overall, 16.2% of patients discontinued rucaparib due to TEAEs. Management of AEs that may occur during rucaparib treatment is crucial for patients to obtain optimal clinical benefit by remaining on therapy and to avoid their detrimental impact on quality of life.

Age-Related Differences in Severe Adverse Events During Maintenance Therapy with PARP Inhibitors: A Retrospective Cohort Study in Japanese Patients with Ovarian Cancer

Advanced ovarian cancer carries a poor prognosis despite standard surgery and chemotherapy. Although poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib and niraparib, have recently become standard maintenance therapy, they can cause hematologic and non-hematologic toxicities, and data on their safety in older Japanese patients are limited. We aimed to evaluate the incidence of clinically significant severe adverse events (SAEs), treatment interruptions, and discontinuation of PARP inhibitor maintenance therapy according to age in Japanese patients with ovarian cancer. This retrospective cohort study used data from the Japanese Diagnosis Procedure Combination database. Patients diagnosed with ovarian cancer who received treatment with PARP inhibitors approved in Japan (olaparib, olaparib plus bevacizumab, or niraparib) after surgery and chemotherapy were included. Clinically significant SAEs were identified using diagnostic and billing codes rather than laboratory-confirmed Common Terminology Criteria for Adverse Events (CTCAE) grading. Outcomes were assessed across two age groups (< 65 vs. ≥ 65 years) using inverse probability weighting to account for baseline differences. After adjustment, the baseline characteristics were balanced among the 1083 patients included in this study (olaparib, 315; olaparib plus bevacizumab, 343; niraparib, 425). In the olaparib group, patients aged ≥ 65 years showed a higher incidence of clinically significant neutropenia compared with those aged < 65 years (incidence rate ratio 7.47; 95% confidence interval 2.37-23.5). In contrast, no significant age-related differences were observed in the incidence of other clinically significant SAEs. Rates of hospitalization, treatment interruption, and treatment discontinuation were generally comparable between the age groups across all regimens. Overall, PARP inhibitor maintenance therapy appeared to be generally tolerated in older patients in this real-world cohort. However, older individuals who received olaparib monotherapy experienced a significantly higher incidence of clinically significant neutropenia, indicating the need for careful monitoring and individualized dose management in this subgroup.

Cost-Effectiveness Analysis of Biomarker Testing to Guide First-Line PARP Inhibitor Maintenance for Patients with Advanced Ovarian Cancer After Response to First-Line Platinum Chemotherapy in the USA

Poly(ADP-ribose) polymerase inhibitor maintenance treatments are available for platinum-sensitive advanced ovarian cancer. Olaparib (O) is available for BRCA mutation patients or in combination with bevacizumab (O+B) for patients with homologous recombination deficiency (HRD+); niraparib (N) is available for all patients. This study aimed to evaluate the cost effectiveness of biomarker testing and maintenance treatments (mTx) with poly(ADP-ribose) polymerase inhibitor in platinum-sensitive advanced ovarian cancer in the USA. Ten strategies were evaluated (S1-S10), representing biomarker testing (none, BRCA or HRD), and mTx (O, O+B, N or B). PAOLA-1 data were used to build a model estimating progression-free survival (PFS), second PFS (PFS2) and overall survival for O+B. PFS was modelled through mixture cure models; PFS2 and overall survival were modelled by standard parametric models. Hazard ratios of PFS for O+B versus B, N and O were obtained from the literature to estimate PFS for B, N and O. PFS2 and OS for B, N and O were informed by PFS benefits. S2 (no testing, B) had the lowest cost while S10 (HRD testing, O+B for HRD+ and B for HRD-) had the highest quality-adjusted life-years (QALYs). All niraparib strategies were dominated. S2, S4 (BRCA testing, O for BRCA+ and B for BRCA-), S6 (BRCA testing, olaparib plus bevacizumab for BRCA+ and bevacizumab for BRCA-) and S10 were the non-dominated strategies with an incremental cost-effectiveness ratio of $29,095/QALY, $33,786/QALY and $52,948/QALY for S4 versus S2, S6 versus S4 and S10 versus S6, respectively. Homologous recombination deficiency testing followed by O+B for HRD+ and B for HRD- is a highly cost-effective strategy for patients with platinum-sensitive advanced ovarian cancer. A HRD biomarker-guided approach provides most QALYs with good economic value.

Efficacy and Safety of Niraparib as First-Line Maintenance Treatment for Patients with Advanced Ovarian Cancer: Real-World Data from a Multicenter Study in China

Poly (ADP-ribose) polymerase (PARP) inhibitors are a new maintenance therapy option for patients with ovarian cancer (OC). To evaluate the efficacy and influencing factors of the novel PARP inhibitor niraparib for maintenance treatment of Chinese patients with advanced OC. In this retrospective multicenter real-world study patients with advanced OC from 15 hospitals throughout China were enrolled. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included the time to treatment discontinuation and safety. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify possible risk factors for PFS, after which a prediction model was established to evaluate the likelihood of achieving an 18-month PFS. The relationship between the dose of niraparib and PFS was also evaluated. The PFS rates of 199 patients at 6, 12, 18, 24, and 30 months were 87.4%, 75.9%, 63.6%, 56.1%, and 51.8%, respectively. LASSO regression model revealed that only age < 65 years (P = 0.011), BRCA mutations (P < 0.001), and R0 status after cytoreductive surgery (P = 0.01) were significant factors associated with prolonged PFS times. Based on the LASSO logistic regression analysis, a clinical prediction formula was developed: - 2.412 + 1.396Age For Chinese OC patients, niraparib, particularly at a 200 mg individual starting dose, was an effective therapy with easily manageable safety.

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer

Niraparib (Zejula™) is a PARP inhibitor which is approved for maintenance therapy in adults with advanced ovarian cancer in complete or partial response to platinum-based chemotherapy. In a placebo-controlled phase III trial in patients with newly diagnosed advanced ovarian cancer, niraparib significantly extended progression free survival in two predefined populations, namely a patient population with altered homologous-recombination DNA repair pathways [i.e. homologous-recombination deficiency positive (HRd)] and the overall trial population. A prespecified exploratory subgroup analysis indicated that niraparib was also efficacious in patients who were homologous recombination deficiency negative or homologous recombination proficient (HRp). Niraparib has a manageable tolerability profile with myelosuppression as the main safety concern. Haematological reactions were managed with monitoring and dose reduction or interruption. A weight- and platelet count-based individualised dosage regimen introduced during the trial (and subsequently approved) appeared to improve haematological tolerability. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer in adults who responded to platinum-based chemotherapy, regardless of homologous-recombination deficiency status and is a promising option for HRp patients, for whom maintenance treatment options are limited.

BRCA1 Expression by Immunohistochemistry and Prognosis in Ovarian Cancer: A Systematic Review and Meta-Analysis

Homologous recombination deficiencies are associated with increased platinum sensitivity and potential response to poly (ADP-ribose) polymerase inhibitors in epithelial ovarian cancer. As an alternative to germline testing or somatic tumor sequencing, BRCA1 deficiency can be detected by immunohistochemistry and might predict homologous recombination deficiencies. This study aimed to assess the association between BRCA1 expression by immunohistochemistry and the prognosis of patients with epithelial ovarian cancer. We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We searched PubMed, EMBASE, Web of Science, and Scopus databases through July 2019. Reference lists of selected articles were screened for further studies. We conducted qualitative synthesis and meta-analyses of hazard ratios for overall survival and progression-free survival. Of 41 studies of BRCA1 expression using immunohistochemistry, 18 evaluated the association of BRCA1 expression with patient survival (2738 cases). The loss of BRCA1 expression was associated with improved overall survival (hazard ratio = 0.67, 95% confidence interval 0.57-0.77) and progression-free survival (hazard ratio = 0.70, 95% confidence interval 0.58-0.84). Negative BRCA1 expression assessed by immunohistochemistry was associated with a better prognosis in epithelial ovarian cancer.