Olaparib Maintenance Research Articles

Durvalumab plus paclitaxel/carboplatin plus bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance among patients with newly-diagnosed advanced ovarian cancer without a tumor BRCA1/BRCA2 mutation: Updated results from DUO-O/ENGOT-OV46/GOG-3025 Trial

Durvalumab plus paclitaxel/carboplatin plus bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance among patients with newly-diagnosed advanced ovarian cancer without a tumor BRCA1/BRCA2 mutation: Updated results from DUO-O/ENGOT-OV46/GOG-3025 Trial

Exploring the impact of BRCA1 and BRCA2 mutation type and location on Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer patients: A single center report

ObjectiveIn patients with platinum-sensitive relapsed ovarian cancer (PSROC) harboring pathogenic/likely pathogenic variants (PV) in BRCA1 and BRCA2 genes, olaparib maintenance monotherapy (OMT) is a viable option. Our study aimed to evaluate the impact of different BRCA1/2 PV in survival outcomes and safety of OMT in BRCA1/2-mutated PSROC patients, focusing on the type and location of PV. MethodsWe assessed the outcomes of 100 BRCA1/2-mutated PSROC patients treated at our institute, analyzing progression-free survival (PFS) and overall survival (OS). Germline and tumor BRCA1/2 genotyping was conducted using Illumina's next-generation sequencing (NGS). ResultsPFS and OS were significantly shorter in PSROC patients with PV in BRCA1 compared to those with PV in BRCA2 (PFS:14.0 vs. 38.8 months, p = 0.007, OS: 21.8 vs. 62.0 months, p = 0.011). Notably, there was a significant difference in PFS based on the intragenic location of BRCA1 PV, with shorter PFS in patients with 1st/2nd relapse, harboring PV in BRCA1 RING domain compared to those with PV in the DNA binding domain (DBD) and BRCT domains (12.4 vs. 23.0 months, p = 0.046). No differences in PFS and OS were observed between patients with germline versus somatic BRCA1/2 PV (PFS:14.9 vs.19.3, p = 0.316, OS: not reached vs. 25.8 months; p = 0.224). However, there were significant differences in the reasons for OMT discontinuation between patients with germline and somatic BRCA1/2 PV, primarily due to adverse side effects. ConclusionsIn summary, the type and location of BRCA1 and BRCA2 PV provide additional insight into the expected survival outcomes of olaparib MT in PSROC patients.Trial registration number: ISRCTN42408038, Name of registry: ISRCTN registry, Date of registration: 24/11/2015.

Clinical and molecular determinants of response to maintenance olaparib for primary and recurrent epithelial ovarian carcinoma

Clinical and molecular determinants of response to maintenance olaparib for primary and recurrent epithelial ovarian carcinoma

Real-world time-to-event outcomes among patients with ovarian cancer receiving olaparib maintenance therapy in the United States

Real-world time-to-event outcomes among patients with ovarian cancer receiving olaparib maintenance therapy in the United States

MA11.07 Pembrolizumab Plus Maintenance Olaparib as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 KEYLYNK-006 Study

MA11.07 Pembrolizumab Plus Maintenance Olaparib as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 KEYLYNK-006 Study

751P Safety and tolerability of durvalumab (D) + carboplatin/paclitaxel (CP) + bevacizumab (B) followed by D, B + olaparib (O) maintenance (mtx) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumour BRCA1/BRCA2 mutation (non-tBRCAm) in the phase III DUO-O trial

751P Safety and tolerability of durvalumab (D) + carboplatin/paclitaxel (CP) + bevacizumab (B) followed by D, B + olaparib (O) maintenance (mtx) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumour BRCA1/BRCA2 mutation (non-tBRCAm) in the phase III DUO-O trial

1504MO Phase II trial of Pembrolizumab and OLApaRib (POLAR) maintenance for select patients (pts) with metastatic pancreatic cancer (mPC) with (A) homologous recombination deficiency (HRD), (B) non-core HRD (ncHRD) and (C) exceptional response to platinum

1504MO Phase II trial of Pembrolizumab and OLApaRib (POLAR) maintenance for select patients (pts) with metastatic pancreatic cancer (mPC) with (A) homologous recombination deficiency (HRD), (B) non-core HRD (ncHRD) and (C) exceptional response to platinum

772P Olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (C-PATROL): Analysis by BRCA mutation status from a real-world study

772P Olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (C-PATROL): Analysis by BRCA mutation status from a real-world study

781P Olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (C-PATROL): Overall survival (OS) in predefined subgroups

781P Olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (C-PATROL): Overall survival (OS) in predefined subgroups

Clinical significance of germline breast cancer susceptibility gene (gBRCA) testing and olaparib as maintenance therapy for patients with pancreatic cancer

BackgroundGermline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy.MethodsWe retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records.ResultsThe median patient age was 64 y (29–85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8–87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1–30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months.ConclusionsThe gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer.

Case report of two long term ovarian cancer survivors with brain metastases following multimodal treatment including chemotherapy, radiotherapy and maintenance olaparib: An institutional case series and literature review

Brain metastasis from ovarian cancer is a very rare condition with a poor prognosis. However, due to its rarity, there is no established treatment strategy. We present a case series of brain metastasis with ovarian cancer, focusing on two long-term survivors treated with multimodal therapy. Among the nine cases, the median survival time after brain metastases was six months (range: 0–58 months). Eight patients had high-grade serous carcinoma (HGSC). Three of the four patients who underwent genetic testing tested positive for germline BRCA2 (gBRCA2) mutation. Two patients survived longer than 4 years after the diagnosis of brain metastases. Both of these patients received chemotherapy, radiation therapy, and olaparib, a molecularly targeted drug, as maintenance therapy. This case series suggests that patients with gBRCA2 mutation-positive HGSC may be at a high risk of developing brain metastases. A multidisciplinary approach, including PARP inhibitors, may improve the prognosis of patients with brain metastases from ovarian cancer.

54P Real-world data of patients with recurrent BRCA-mutated platinum-sensitive ovarian cancer treated with olaparib maintenance: Surgical outcome subgroup analysis from the C-PATROL study

54P Real-world data of patients with recurrent BRCA-mutated platinum-sensitive ovarian cancer treated with olaparib maintenance: Surgical outcome subgroup analysis from the C-PATROL study

Real-world clinical outcomes and prognostic factors of olaparib maintenance in Korean patients with primary or recurrent high-grade ovarian cancer with exploratory analysis of location of BRCA1 and BRCA2 mutations.

e17561 Background: Olaparib is approved for first-line (1L) and second or subsequent-line (2L+) maintenance therapy in BRCA-mutated ovarian cancer (OC). However, the correlation between location of BRCA mutation and benefit of olaparib maintenance therapy has not been thoroughly investigated. We aimed to analyze real-world clinical outcomes and identify prognostic factors for olaparib maintenance therapy in Korean patients with BRCA-mutated OC, focusing on BRCA mutation sites. Methods: This retrospective cohort study included Korean patients with BRCA-mutated OC who received olaparib as 1L or 2L+ at the single center between January 2015 and April 2023. Survival outcomes and toxicity were correlated with BRCA mutation location summaries and patient characteristics by maintenance therapy line. Results: For the 1L group (n = 70), 2-year PFS and 3-year OS were 75.5% (95% CI, 56.4–87.1) and 98.5% (95% CI, 90.0–99.8). For the 2L+ group (n = 83), 2-year PFS and 3-year OS were 54.8% (95% CI, 56.4–87.1) and 87.3% (95% CI, 76.7–93.3). Primary stage (IV vs. ≤ III) was a prognostic factor for PFS in the 1L group (adjusted hazard ratio [aHR], 5.74; 95% CI, 1.23–26.73; P = 0.026). Notably, Korean-specific pathogenic variant p.Leu1780Pro BRCA1 mutation carriers (n= 8) showed significantly worse PFS than non-carriers (n = 32) in the 1L group (Log-rank P = 0.014). For the 2L+ group, platinum-free interval ≥ 12 months was a good prognostic factor for both PFS (aHR, 0.42; 95% CI, 0.23–0.75) and OS (aHR, 0.31; 95% CI, 0.11–0.91). Additionally, somatic BRCA1 mutation was a poor prognostic factor for PFS in the 2L+ group (hazard ratio [HR], 3.39; 95% CI, 1.22–9.38; P = 0.029). In the 1L group, the longer interval between the last chemotherapy and maintenance therapy was associated with the lower risk of hematologic toxicity induced by olaparib (odd ratio [OR], 0.75; 95% CI 0.57–0.99; P = 0.04). In addition, age ≥ 65 years (OR, 3.33; 95% CI, 1.05–10.63; P = 0.04) and the dose reduction of the last chemotherapy (OR, 3.80; 95% CI, 1.02–14.18; P = 0.047) were associated with a higher risk of hematologic toxicity in the 1L group. In the 2L+ group, germline BRCA1 (OR, 0.36; 95% CI, 0.14–0.92; P = 0.03) and BRCA2 (OR, 7.47; 95% CI, 1.96–28.39; P = 0.003) mutations showed contrariwise risks for hematologic toxicity. Drug discontinuation due to toxicity was 1.4% and 6.0% in the 1L and the 2L+ groups and no acute myeloid leukemia/myelodysplastic syndrome cases were observed. Conclusions: Olaparib maintenance therapy was effective and tolerable in Korean patients with BRCA-mutated OC. Prognostic factors for survival outcomes and risk factors of hematologic toxicity in olaparib maintenance therapy were different between 1L and 2L+. The prognostic significance of Korean-specific p.Leu1780Pro BRCA1 mutation on olaparib should be further researched.

Overall survival in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance: Real-world data of the C-PATROL study.

e17542 Background: Maintenance monotherapy with PARP-inhibitor (PARPi), olaparib has previously shown good effectiveness and tolerability in total population of patients with PSROC who were in response to platinum-based chemotherapy (PBC) in the C-PATROL study. Here we present the overall survival (OS) data in different subgroups. Methods: The prospective German non-interventional study C-PATROL (NCT02503436) captured routine clinical data of olaparib maintenance according to label in patients with BRCA-mutated PSROC treated with PBC. The primary endpoint was PFS, relevant secondary endpoints included OS and safety. Data were analyzed by descriptive statistics. Results: Between 10/2015 and 10/2019, 277 patients were enrolled. The ITT set (study selection criteria fulfilled) comprised 267 patients (median age: 60 yrs; ECOG ≤1: 93%; ≥2 relapses: 32%; ≥3 prior PBC: 29%). Median follow-up was 23.5 months (range 0.0–80.5) and median olaparib treatment duration was 13.6 months (0.1–80.9). 10% of patients received olaparib for ≥ 5 years and 8% of patients received further PARPi also as subsequent treatment. Median OS was 35.4 months (95% CI 29.2–49.9). The longest median OS was observed in patients with a complete debulking after the surgery at current relapse, a complete response (CR) to the current PBC and a BRCA2 mutation. Adverse events (AEs) were consistent with the known tolerability profile of olaparib (safety set: n=274; any AE: 95%, AE of CTCAE grade ≥ 3: 40%, olaparib discontinuation due to AE: 11%; most common AE any CTCAE: nausea (46%), fatigue (39%), anaemia (31%), and vomiting (17%); most common AE CTCAE grade ≥ 3: anaemia (14%)). Conclusions: Olaparib is effective and safe in the real-world setting. In olaparib-treated patients with BRCA-mutated PSROC longer OS was observed mainly with respect to resection status after debulking surgery at current relapse, to tumor burden at the therapy start and BRCA mutation type. Our data underline the role of cytoreduction and platinum response in the context of PARPi maintenance therapy. Clinical trial information: NCT02503436 . [Table: see text]

43O Durvalumab (D) + carboplatin/paclitaxel (CP) + bevacizumab (B) followed by D, B + olaparib (O) maintenance (mtx) for newly diagnosed advanced ovarian cancer (AOC) without a tumour BRCA1/BRCA2 mutation (non-tBRCAm): Updated results from DUO-O

43O Durvalumab (D) + carboplatin/paclitaxel (CP) + bevacizumab (B) followed by D, B + olaparib (O) maintenance (mtx) for newly diagnosed advanced ovarian cancer (AOC) without a tumour BRCA1/BRCA2 mutation (non-tBRCAm): Updated results from DUO-O

Overall survival (OS) in patients with platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance monotherapy: Update from the L-MOCA trial.

Overall survival (OS) in patients with platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance monotherapy: Update from the L-MOCA trial.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells wasassociated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. NCT03534453. Registered at May 23, 2018.

Olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer at a single institution: A retrospective study.

In this study, we aimed to investigate patient characteristics, efficacy, prognostic factors, and safety of olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer at our institution. Patients responding to platinum-based therapy and starting olaparib maintenance therapy for recurrent epithelial ovarian, fallopian tube, or peritoneal cancer at Kurume University Hospital between January 2018 and November 2021 were enrolled in the study. Their data were extracted retrospectively from medical records. In all, 50 patients were included. The median (range) age of the patients, follow-up time, and duration of olaparib maintenance therapy were 62 (39-87) years, 21.6 (2.2-45.9) months, and 7.2 (2-45.9) months, respectively. Among the 29 patients tested for homologous recombination (HR) status, 22 (75.9%) were positive for HR deficiency (HRD), 12 (54.5%) of whom had BRCA-positive tumors. The median progression-free survival was 8.9 months (95% confidence interval: 6.2-12.6), and the median overall survival was 27.1 months (95% confidence interval: 22.5-40.3). Multivariate analysis of prognostic factors revealed that HRD was an independent prognostic factor for both progression-free survival and overall survival. The most common adverse event was nausea (any grade, n = 30, 60%), resulting in drug interruption (n = 23, 46%), dose reduction (n = 17, 34%), and discontinuation of treatment (n = 1, 2%). Olaparib maintenance therapy for recurrent platinum-sensitive ovarian cancer at our institution was effective, with acceptable adverse events. HRD was the most significant prognostic factor for patients with recurrent platinum-sensitive ovarian cancer.

Familial and hereditary pancreatic cancer in Japan.

As in Western countries, familial pancreatic cancer accounts for 5-7% of pancreatic cancer (PC) in Japan. Opportunities for diagnosing hereditary pancreatic cancer (HPC) are increasing owing to the coverage of companion diagnostics and cancer genomic profiling by national health insurance in patients with unresectable or recurrent PC refractory to standard chemotherapies. HPC is recognized in 7% of PCs and 15% of familial pancreatic cancer, including germline variants of BRCA1/2, ATM, PALB2, APC, and mismatch repair genes. Individuals with 5-fold or greater inherited risks of PC are recommended to undergo pancreatic surveillance according to Japanese guidelines. The imaging modalities for this surveillance include endoscopic ultrasound, magnetic resonance cholangiopancreatography, abdominal ultrasound, and enhanced computed tomography. Currently, a nationwide prospective surveillance study is ongoing in Japan. Platinum-based chemotherapy is an effective pancreatic cancer treatment in patients with variants of homologous recombination repair genes (BRCA1/2 and PALB2); however, the use of platinum regimens solely based on familial/personal cancer history remains controversial. The efficacy of olaparib maintenance therapy, as confirmed by the POLO study, has significantly impacted the clinical treatment of advanced PC patients in Japan. Since the initiation of precision cancer medicine in 2019, genetic medicine for PC patients has expanded in Japan.

Olaparib Addition to Maintenance Bevacizumab Therapy in Ovarian Carcinoma With BRCA-Like Genomic Aberrations

Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing. To investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile. This cohort study was a secondary analysis of the PAOLA-1 randomized clinical trial that compared olaparib plus bevacizumab with placebo plus bevacizumab as maintenance treatment in patients with advanced high-grade ovarian cancer after a good response to first-line platinum with taxane chemotherapy plus bevacizumab, irrespective of germline or tumor BRCA1/2 mutation status. All patients with available tumor DNA were included in the analysis. The current analysis tested for an interaction between BRCA-like status and olaparib treatment on survival outcomes. The original trial was conducted between July 2015 and September 2017; at the time of data extraction for analysis in March 2022, a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up time of 21 711 months was available, with 336 PFS and 245 OS events. Tumor homologous recombination deficiency was assessed using the BRCA-like copy number aberration profile classifier. Myriad MyChoice CDx was previously measured. The trial was randomized between the olaparib and bevacizumab and placebo plus bevacizumab groups. This secondary analysis assessed hazard ratios (HRs) of olaparib vs placebo among biomarker strata and tested for interaction between BRCA-like status and olaparib treatment on PFS and OS, using Cox proportional hazards regression. A total of 469 patients (median age, 60 [range 26-80] years) were included in this study. The patient cohort consisted of women with International Federation of Gynaecology and Obstetrics stage III (76%) high-grade serous (95%) ovarian cancer who had no evaluable disease or complete remission at initial or interval debulking surgery (76%). Thirty-one percent of the tumor samples (n = 138) harbored a pathogenic BRCA mutation, and BRCA-like classification was performed for 442 patients. Patients with a BRCA-like tumor had a longer PFS after olaparib treatment than after placebo (36.4 vs 18.6 months; HR, 0.49; 95% CI, 0.37-0.65; P < .001). No association of olaparib with PFS was found in patients with a non-BRCA-like tumor (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93). The interaction was significant (P = .004), and HRs and P values (for interaction) were similar in the relevant subgroups, OS, and multivariable analyses. In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.