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5544 Background: In ARIEL3 (NCT01968213), rucaparib maintenance treatment led to significant improvement vs placebo for the primary endpoint of investigator-assessed progression-free survival (PFS) in patients (pts) with platinum-sensitive, recurrent ovarian carcinoma responsive to the last line of platinum therapy (Coleman et al. Lancet. 2017;390:1949–61). The largest benefit was observed in pts with carcinomas with a BRCA mutation or high loss of heterozygosity (LOH), a marker of homologous recombination deficiency (HRD). However, rucaparib also improved PFS in pts with carcinomas negative by HRD test (ie, BRCA wild-type with low LOH), a subset of pts for which there is no identified molecular mechanism conferring PARP inhibitor sensitivity. Among these pts (rucaparib, n = 107; placebo, n = 54), median PFS was 6.7 vs 5.4 months, respectively (HR, 0.58 [95% CI 0.40–0.85]; P= 0.0049), and 31.8% vs 4.3% were progression-free at 1 yr. In this post hoc exploratory analysis, we further evaluated the efficacy of rucaparib maintenance vs placebo in this subset of pts. Methods: Pts were randomized 2:1 to oral rucaparib (600 mg BID) or placebo. For this analysis, investigator-assessed PFS and safety were evaluated in pts with HRD-negative carcinoma, defined as BRCA wild-type with genomic LOH < 16% using Foundation Medicine’s T5 NGS assay. Results: Visit cutoff dates for efficacy and safety were Apr 15, 2017, and Dec 31, 2019. Across subgroups based on demographic or disease characteristics, the trend of rucaparib benefit vs placebo was consistently observed in pts with HRD-negative carcinoma (Table). The safety profile of rucaparib in the HRD-negative population was consistent with that of the overall safety population reported previously. Conclusions: Rucaparib maintenance reduced risk of progression in pts with ovarian carcinomas, including those not associated with HRD, regardless of clinical prognostic factors. [Table: see text]

5554 Background: Antibodies targeting PDL1 or PD1 have been disappointing so far in the treatment of ovarian cancer (OC). A greater understanding of the complex iTME and of the impact of chemotherapy on immune features could uncover promising immune targets. We previously reported that neoadjuvant chemotherapy (NACT) increased CD4+ and CD8+ immune cells (IC) and depleted FOXP3+ suppressive T-regs in OC iTME. Here we aimed to describe the expression of PDL1 as well as other co-regulatory molecules in OC and their changes under NACT. Methods: Tumor samples and clinical data were prospectively collected from patients (pts) in the randomized CHIVA trial of NACT +/- nintedanib. Samples were evaluable for immune profiling for 116-124 pts at diagnosis and 89-107 at surgery after 3 cycles of NACT. IC stained for CD4, CD8 were scored as number of IC+/mm². Expression of immune co-regulatory molecules PDL1, TIM3, LAG3 and IDO was scored as percentage of positive cells, and tumors were classified as PDL1/TIM3/IDO/LAG3 positive if > 1% of IC and/or tumor cells (TC) were positive. Highly sensitive pts, defined as objective response to NACT and prolonged median progression-free survival (mPFS > 24months), were compared to refractory pts (progressing during or within 3mo of platinum). Results: As expected, about one third (36%) of tumors were PDL1+ at diagnosis. In contrast, the prevalence of other co-regulatory molecules was higher with 52%, 54% and 93% of tumors being positive for IDO, LAG3 and TIM3, respectively. There was no significant change in PDL1 expression with NACT. However, in paired samples NACT significantly increased IDO and LAG3 expression (p < 0.05), such that 60% and 66% of tumors post-NACT were positive for IDO and LAG3, respectively. TIM3 expression remained high post-NACT with 92% of positive tumors. Highly sensitive tumors (vs refractory tumors) had significantly higher IC expression of TIM3 after NACT (24% vs 6%, p = 0.005), and were significantly more infiltrated by CD4+ (441 vs 228 cells/mm2, p = 0.04) and CD8+ (460 vs 225 cells/mm2, p = 0.045) T cells. Conclusions: Other immune targets beyond PDL1 are highly expressed in OC. In addition NACT appears to prime the iTME by increasing effector T cell infiltration and the expression of other relevant co-regulatory molecules (LAG3, TIM3 and IDO). Future studies could be performed by priming the iTME with NACT and testing novel immune therapies based on target expression in samples obtained at interval debulking surgery.

TPS5614 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunogenic “cold” to “hot” tumors via vaccination with tumor-associated antigens (TAAs). OSE2101 is a multiple-neoepitope vaccine restricted to HLA-A2-positive patients (45% of OC patients) targeting 5 TAAs: TP53, MAGE2, MAGE3, CEA and HER2. These neo-epitopes are modified to increase both major histocompatibility complex and the T cell receptor binding affinity. The proof of concept for this approach was recently demonstrated with OSE2101 improving overall survival in a phase III trial in lung cancer progressing after ICI (Besse et al. 2021). The combination of OSE2101 with an ICI may most effectively harness anti-tumor immunity. Methods: TEDOVA is an international randomized open-label, phase II trial evaluating the benefit of maintenance by OSE2101 alone or in combination with PD1 inhibition (pembrolizumab) after platinum based chemotherapy in relapsed OC, previously treated with bevacizumab (if eligible) and a PARP inhibitor (if eligible). Patients (N=180) with CR/PR/SD at the end of chemotherapy are randomized (1:1:2) to: Observation/BSC (Arm A), OSE2101 alone (Arm B), or OSE2101 in combination with pembrolizumab (Arm C). Experimental treatments are continued until progression, or intolerance, for up to 2 years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, safety, time to subsequent first or second treatment (TTST-1, TTST-2) and overall survival. 180 HLA-A*02 positive patients will be randomized. HLA-A*02 negative patients will be followed in a separate observational cohort. The sample size is calculated to provide 90% power to detect an improvement in PFS for Arm C vs Arm A with a HR of 0.57. Three one-sided Log-rank tests will be considered in a pre-defined sequence: H1: C (OSE2101+pembrolizumab) vs A (BSC); H2: C (OSE2101+pembrolizumab) vs B (OSE2101) and H3: B vs A. The type I error will be α=5%. The type II error will be β=10%. Tests will be one-sided. Status: The TEDOVA/GINECO-OV244b/ENGOT-ov58 trial is currently recruiting. Clinical trial information: NCT04713514.

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) < 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.

5513 Background: Homologous recombination deficiency (HRD), defined as BRCA1/2 mutation ( BRCAmut)or high genomic instability, is currently used to identify patients (pts) with epithelial ovarian cancer (EOC) most likely to benefit from PARP inhibitors. While these genomic tests are useful, they are imperfect: some BRCAm EOC demonstrate primary PARPi resistance and some HR-proficient benefit. Another approach to evaluate HRD is to measure the capacity of tumor cells to recruit nuclear RAD51 foci during S/G2 phase in the presence of double strand DNA damage using multiplexed immunofluorescence (IF) for RAD51, geminin (GMN) and yH2AX. We aimed to describe for the 1st time HRD using this RAD51 functional assay in EOC and correlate RAD51 status to platinum response and BRCAmut. Methods: Tumor samples and clinical data were collected prospectively from pts in the randomized CHIVA trial of neoadjuvant platinum chemotherapy +/- nintedanib. IF for RAD51, GMN, and DAPI was performed on a 3uM slide from FFPE blocks, where feasible, yH2AX was positively scored on a consecutive slide. Tumors were considered RAD51-deficient if < 10% of gem+ tumor cells (TC) had > 5 RAD51+ foci. BRCAmut were identified by NGS. Results: 155 baseline chemotherapy naïve EOC samples were available. All were advanced stage (IIIC/IV), 75% were G3, 7% G2, 2% G1, and 16% grade UK. A contributive RAD51 result was obtained for 90% (139/155) of samples. Contributive NGS results were available for 130 samples. Overall, yH2AX scores were high (median % TC+: 86%, IQR: 56%-100%) confirming the presence of significant basal DNA damage in high grade EOC. Only 8 samples were yH2AX-low, including two of the three G1 tumors. In contrast, 55% (76/155) of samples were considered RAD51-deficient (score < 10%). With regard to outcome, pts with RAD51-deficient tumors had significantly higher overall response rates to neoadjuvant platinum (68% vs 37%, p = 0.04) and significantly longer median progression-free survival (HR 0.50, IC95% 0.25-0.98, p = 0.02). Considering BRCA status, 15% of tumors harbored a deleterious BRCAmut and 67% of these were RAD51-deficient. Importantly among BRCAmut EOC, the RAD51-proficient tumors had significantly poorer response to neoadjuvant chemotherapy (RR = 17% vs 75%, p = 0.02). Conclusions: We evaluated a novel functional assay of HR functionality in advanced EOC. The assay requires minimal tissue and yields contributive results in 90% of cases. Overall, EOC demonstrate high levels of basal DNA damage, yet 55% fail to recruit RAD51 foci during S/G2 cell cycle phase. These RAD51-deficient EOC have improved outcome after neoadjuvant platinum. Conversely, the RAD51 assay also identified a small subset of RAD51-high BRCAmut tumors with poor platinum response. Whether this RAD51 functional assay may also predict PARP inhibitor benefit is currently being investigated.

5522 Background: There is a medical unmet need for effective treatments in platinum resistant ovarian cancer patients. We assessed the safety and efficacy of a combination of pembrolizumab with bevacizumab and pegylated liposomal doxorubicin (PLD). Methods: This is an open-label phase 1b trial in patients ECOG 0 or 1 with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The safety of the dual combinations of pembrolizumab with bevacizumab or with PLD were previously evaluated in 6 patients respectively. In the absence of dose limiting toxicities (DLT) the triple combination was evaluated at a maximum tolerated dose (MTD)-1 for PLD in 3 patients and in the absence of DLT at MTD. The sample size was calculated according to the modified toxicity probability interval design. The primary evaluation criteria was the safety, the secondary endpoint was the outcome. Pharmacokinetics of the flat dose of bevacizumab will be evaluated. Results: 22 patients were enrolled from September 2019 until June 2020 in six French centers. 3 initial patients have been treated at 20mg/m2 of PLD (MTD-1) and 19 patients were treated at the dose of 30mg/m2 of PLD (MTD) combined with 200mg of pembrolizumab until progression, unacceptable toxicity, or withdrawal of consent and 400mg of bevacizumab for a total of six cycles. The patients’ characteristics are reported in the table. No DLT occurred. Grade 3 palmar-plantar erythrodysesthesia were reported in 4 patients. The recommended phase II dose of PLD was 30mg/m2 in combination with pembrolizumab and bevacizumab. For patients treated at MTD, the overall response rate was 32% (6 partial responses) with 74% of clinical benefit with a durable response in 10 patients (53%). Median number of cycles was 7.5 (2 to not reached). Two patients are still on treatment. Correlative studies are ongoing. Conclusions: The combination was well tolerated and demonstrated clinical benefit in 74% platinum resistant ovarian cancer patients with durable response (>6 months) in 53% of patients. Clinical trial information: NCT03596281. [Table: see text]

5537 Background: ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients (pts) who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Methods: Pts were randomized 2:1 to receive rucaparib 600 mg BID or placebo. At the data cutoff of Dec 31, 2019, 33/375 (9%) and 1/189 (0.5%) pts were still ongoing and receiving rucaparib or placebo, respectively. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between pts who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term [ST] subgroup) within each treatment arm. Results: Of 564 pts, 83 (15%) showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm. Within the rucaparib arm, exceptional benefit pts had more favorable clinical prognostic factors at baseline compared with the ST subgroup (Table). While BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 34/79 (43%) of these pts were BRCA wild type. Among other biomarkers, RAD51C/D mutations were associated with exceptional benefit; low genome-wide loss of heterozygosity was enriched within the ST subgroup; and high BRCA1 methylation was present at similar fractions. Trends were similar in the placebo arm (Table). Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, pts with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of HGOC pts. Clinical trial information: NCT01968213. [Table: see text]

6011 Background: The neoadjuvant setting is an excellent opportunity to study ‘ in vivo’ the biological impact of treatment on tumor cells and the immune TME. Both chemotherapy and anti-angiogenics may have immunomodulatory properties which could prime the TME and increase effectiveness of immunotherapeutic agents. We performed comprehensive multiplexed immune biomarker analyses on paired tumor samples at diagnosis and after 3 cycles of neoadjuvant carboplatin+paclitaxel (CP) +/- the anti-angiogenic tyrosine kinase inhibitor nintedanib (N) in the randomized CHIVA trial. Methods: Patients were randomized 2:1 to CP + N or placebo for 3 cycles prior to interval debulking, samples were evaluable for immune profiling for 124 pts at diagnosis and 107 at surgery from the CHIVA trial. For 86 patients matched paired samples were available. Multiplexed IF or IHC panels were performed for CD4, CD3, CD8, CK, Granzyme B, FOXP3, CD68, CD163 and DC-Lamp. Wilcoxon tests were used to compare measurements. Results: At diagnosis the most abundant cells were CD8+ and CD4+ cells (median=118 and 119cells/mm2, respectively) compared to Foxp3+ TRegs (median=30/mm2). Among the myeloid lineage, the proportion of CD68+ (M1) and CD163+ (M2) macrophages was balanced, while mature dentritic cells (DC) represented

6066 Background: Knowledge regarding HRD status is becoming crucial to guide maintenance strategies for patients with newly diagnosed OC. Unfortunately, for patients (pts) treated with neoadjuvant chemotherapy (NACT), HRD testing on small biopsies from diagnostic laparoscopies (Dx Lap) or interval debulking has a high failure rate. At relapse, biopsies may not be feasible. Aim: Evaluate the feasibility and usefulness of HRD testing on cfDNA from ascites Methods: Pts enrolled in a prospective biological study (OvBIOMark) consented to analysis of biological samples obtained as part of routine diagnosis. cfDNA was extracted from 1-2ml of double-centrifuged fresh ascites and subjected to 1) targeted NGS including the most common somatic mutations in high grade ovarian cancer ( TP53) to confirm presence of tumor cfDNA and 2) SNParray for copy number (CN) analyses to calculate a genomic instability score (GIS) for HRD. Results: Thirty four ascites samples were collected from 25 pts with suspected or confirmed OC. For 15/25 pts samples were obtained at Dx Lap, and for 10 pts samples were obtained at relapse. Seven pts underwent repeat ascitic drains during treatment or at relapse. 97% (33/34) of ascitic samples had detectable cfDNA (median = 980ng, range:80-5730ng) even when obtained during chemotherapy. A deleterious mutation was identified in 87% (29/33) of samples with high allelic frequencies (median allelic frequency, AF = 60%; 3.3-87%), confirming that most of detected cfDNA was tumoral. The most common mutation was a TP53m (86%; 25/29). We have performed CN analysis on cfDNA from ascites on 17 of these patients to evaluate their HRD status. Ten pts had a high GIS (HRD+), and 7 pts a low GIS (HRD-). The 4 pts with confirmed BRCAm included in this study had a high GIS on ascites. When available from the same patient, the CN profiles derived from ascites cfDNA and tumor sampling were superimposable. Conclusions: Ascites yields large amounts of cfDNA, which can be confirmed as tumoral based on TP53 mutation detection. CN analysis on ascitic cfDNA is feasible and can be used to detect the same HRD scar as tumor testing. Ascites is frequent at diagnosis, especially in pts with inoperable disease planned for NACT and could provide a useful alternative to tumor for HRD and BRCA testing.

6015 Background: Pts who derive durable benefit from PARP inhibitor treatment may provide insights into improving outcomes. Here we describe long-term responders from Study 10 (NCT01482715) and ARIEL2 (NCT01891344), studies of the PARP inhibitor rucaparib for the treatment of high-grade recurrent OC. Methods: This analysis included pts enrolled in Study 10 (Part 2A: BRCA1 or BRCA2 [ BRCA]-mutant OC, platinum sensitive, 2–4 prior chemotherapies; Part 2B: any platinum status, 3–4 prior chemotherapies) and ARIEL2 (Part 1: BRCA-mutant or wild-type OC, platinum sensitive; Part 2: any platinum status, 3–4 prior chemotherapies). Final results from Study 10 (n = 54) and ARIEL2 (n = 491) were pooled. Long-term responders were defined as pts with duration of response (DOR) > 1 y, and short-term responders as pts with DOR ≤ 20 weeks; responses were evaluated using RECIST. Targeted next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. BRCA1 methylation was quantified by digital droplet PCR. Results: Overall, 25% (138/545) of enrolled pts were responders. Of these, 29% (40/138) had long-term responses, including 16/138 (12%) with DOR > 2 y; 21% (29/138) were short-term responders. Both groups received a median of 3 prior anticancer therapies. Among patients with BRCA mutations, BRCA homozygous deletion or rearrangement was detected in 15% (4/27) of long-term responders vs 0% (0/15) of short-term responders. In an expanded analysis of the 95 pts with BRCA mutations and confirmed response, pts with BRCA homozygous deletion or rearrangement had significantly longer DOR than pts with other mutation types (median 3.5 vs 0.6 y; HR = 0.30; p = 0.024). There was no apparent difference in BRCA gene or mutation location for long- vs short-term responders. Ten of the 13 long-term responders with BRCA wild-type OC had high genome-wide LOH (≥16% LOH), a genomic scar indicative of homologous recombination deficiency, including OC associated with BRCA1 hypermethylation (n = 2) and RAD51C/D mutations (n = 2). Conclusions: Long-term responders to rucaparib include OC with BRCA mutation, particularly homozygous deletion or rearrangements, which would not be susceptible to somatic reversion mutations, as well as BRCA1 hypermethylation, and RAD51C/D mutations. Clinical trial information: NCT01482715; NCT01891344.

3635 Background: Lurbinectedin (L), an inhibitor of active transcription, has shown activity in second-line (2L) small cell lung cancer (SCLC) (ASCO 2019). Topotecan (T) is the only approved drug in 2L SCLC and is also used in platinum resistant ovarian cancer (PROC). Methods: This pooled safety analysis includes data from 554 patients (pts) treated with L at 3.2 mg/m2 Day 1 q3wk 1-h (no primary prophylaxis with G-CSF required): 335 with selected solid tumors (9 indications, including 105 pts with SCLC) from a phase II Basket study and 219 with PROC in the phase III CORAIL study. An indirect exploratory comparison (pooled data from CORAIL + Basket) and a direct comparison (data from CORAIL) of L vs. T are presented. Results: Most common adverse events with L were grade 1/2 fatigue, nausea and vomiting. Treatment-related (L/T): dose reductions: 22.9/48.3%, delays: 25.8/52.9%, grade ≥3 serious adverse events (SAEs): 15.0/32.2%, discontinuations: 3.2/5.7%, deaths: 1.3/1.5%, G-CSF use: 23.8/70.1%, and transfusions: 15.9/52.9%. Conclusions: Lurbinectedin has a predictable and manageable safety profile. A significant safety advantage was observed when lurbinectedin was compared with topotecan in the CORAIL trial in terms of hematological toxicities. With the limitations of indirect comparisons, in the pooled safety analysis, fewer lurbinectedin-treated pts had severe hematological toxicities, SAEs, dose adjustments, treatment discontinuations and use of supportive treatments than topotecan-treated pts. Clinical trial information: NCT02421588 and NCT02454972 . [Table: see text]

TPS6109 Background: Advanced endometrial cancer (EC) patients relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Data from the TGCA suggest opportunities to targeting DNA repair in women with EC. Particularly type 4 (High copy number or serous like, with frequent TP53 mutations) and type 2 (microsatellite instability hypermutated) EC can be associated with defects in double strand break DNA repair by homologous recombination (HR) and could potentially be targeted by olaparib. We propose a placebo-controlled, multicenter, two-arm, phase II trial comparing olaparib versus placebo in maintenance therapy after chemotherapy in patients with advanced/metastatic EC. Methods: The primary objective of this trial is to evaluate the efficacy of maintenance olaparib in comparison to placebo after platinum based chemotherapy, defined by PFS according to Recist. Key eligibility criteria include: advanced/metastatic histologically confirmed EC (excepted carcino-sarcoma, small cells& neuroendocrine); prior surgery, adjuvant chemotherapy, radiation and hormonal therapy are permitted; objective or stable response after first-line chemotherapy is mandatory. 147 patients are randomized (2:1) after chemotherapy to receive Olaparib 300mg twice daily or placebo in maintenance after at least 4 cycles of platinum based chemotherapy. Olaparib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Stratification is on IHC P53 and MMR status. Primary hypothesis is a 66.7% relative increase in the median PFS rate in the olaparib arm (from 4.5 to 7.5 months), corresponding to a 0.60 Hazard Ratio. Secondary endpoints include PFS according to P53, MMR and NGS HRD status, PFS2, disease specific survival, time to subsequent therapy, overall survival, objective response, disease control rate, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24, EORTC-FA, EQ5D) and safety. Trial is recruiting in France (in February n= 40 randomization). Conclusion: this will be the first study that evaluate the efficacy of olaparib in maintenace after chemotherapy in advanced/metastastic EC, stratified on molecular profil. Clinical trial information: NCT03745950.

2521 Background: Membranous expression of AMHRII is found in ~70% of gynecological tumors. Murlentamab (M) binds with high affinity both AMHRII (at cell membrane) and CD16 (on macrophage, via its low fucose Fc). M reprograms TAMs, restoring their antitumoral functions (phagocytosis) resulting in cytotoxic T cell reactivation. Methods: Pts with advanced/metastatic AMHRII-expressing ovarian, cervical or endometrial cancer with measurable disease and performance status ≤ 1 received M as single agent (SA) in 8 dose escalating and 2 expansion cohorts. Combination with CP was studied in 2 escalating cohorts. Safety, recommended dose determination, antitumor activity, pharmacodynamics (PD) effects (circulating immune cells and tumor microenvironment (TME) from paired biopsies) were assessed. Results: 68 heavily pretreated (median 4 prior lines) pts received M for 0.5 to 11 months (mo) (59 pts M SA and 9 pts M + CP). No dose limiting toxicity was reported. Most common toxicity was G1-2 asthenia (29 %). Eight pts (12%) had G ≥ 3 reversible toxicities (asthenia, nausea/vomiting, anorexia, arthralgia). No antidrug antibody was detected. One partial response (PR) was achieved with M SA in a granulosa pt. In CP combination, 4/9 pts (44%) responded to treatment (1 Complete Response and 3 PRs). Overall, 22/67 (33%) pts were progression-free at 4 mos. Among 17 pts treated ≥ 6 mos, 6/9 (67%) granulosa pts with M SA and 4/5 (80%) endometrium and cervix with CP combination had a longer PFS than under previous regimen. PD blood assessment of 25 pts treated with M SA showed an increase in classical monocytes, and T cells and neutrophils activation. Changes in TME under M will be presented. Conclusions: Murlentamab was very well tolerated, demonstrated immune PD effects and showed hints of antitumor activity. These results together with its innovative immunological mode of action support development of M in AMHRII-expressing cancers, in combination with chemotherapy or other immune oncology drugs. Clinical trial information: NCT02978755.

5541 Background: In SOLO1 (NCT01844986), maintenance olaparib significantly improved progression-free survival (PFS) vs placebo (HR 0.30; 95% CI 0.23–0.41; Moore et al. N Engl J Med 2018) in pts with newly diagnosed advanced OC and a BRCAm. This analysis evaluates olaparib efficacy by timing of surgery, presence of residual tumor following surgery and response status after completion of chemotherapy in SOLO1. Methods: Pts underwent cytoreductive surgery and were in clinical complete response (CR) or partial response (PR) after platinum-based chemotherapy. Pts were stratified by response and received olaparib tablets 300 mg twice daily or placebo. Investigator-assessed PFS and objective response were assessed using modified RECIST v1.1. Results: 260 pts were randomized to olaparib and 131 to placebo; one pt did not receive placebo. Median follow-up was 41 months in both arms. 63% and 35% of pts underwent upfront and interval surgery, 21% and 76% had residual and no residual macroscopic disease after surgery, and 74% and 26% entered the study in clinical CR and PR (based on electronic case report form [eCRF] data). PFS was significantly improved regardless of the timing of surgery, residual disease status after surgery or response after platinum-based chemotherapy (Table). In pts with baseline radiologic evidence of disease (n=80; eCRF), the objective response rate was 43% for olaparib (CR, 28%) and 23% for placebo (CR, 12%). Conclusions: Maintenance olaparib improved outcomes compared with placebo in pts with newly diagnosed advanced OC and a BRCAm, regardless of surgical or tumor status. Clinical trial information: NCT01844986. [Table: see text]

5522 Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-type BRCA/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Exploratory endpoints of time to first subsequent therapy (TFST), time to investigator-assessed PFS on the subsequent line of treatment or death (PFS2), and time to second subsequent therapy (TSST) were assessed in the predefined cohorts. Results: Exploratory efficacy endpoint data are given in the Table. As of Dec 31, 2017, the most common treatment-emergent adverse events (TEAEs) of any grade (rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). The most common grade ≥3 TEAEs were anemia/decreased hemoglobin (21.5% vs 0.5%) and alanine/aspartate aminotransferase increase (10.2% vs 0.0%). Conclusions: Rucaparib significantly improved the clinically meaningful endpoints TFST, PFS2, and TSST vs placebo in all predefined cohorts of pts with platinum-sensitive, recurrent OC. The updated safety profile was consistent with prior reports. Clinical trial information: NCT01968213. [Table: see text]

5551 Background: In SOLO1 (NCT01844986), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations ( BRCA1m) or BRCA2 mutations ( BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2 -mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT01844986. [Table: see text]

5539 Background: In SOLO1 (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit vs placebo in newly diagnosed pts with advanced OC, a BRCAm and clinical complete or partial response to platinum therapy (HR 0.30; 95% CI 0.23–0.41) and was well tolerated (Moore et al. NEJM 2018). We analysed the most common AEs and hematologic AEs in SOLO1. Methods: Pts received olaparib tablets 300 mg twice daily or placebo until progression unless they had no evidence of disease at 2 years, in which case treatment stopped. AEs were graded using CTCAE v4.0. Results: Of 391 pts randomized, 390 (olaparib, 260; placebo, 130) were treated and included in the safety analysis. Median treatment duration was approximately 25 months for olaparib vs 14 for placebo. Median time to first onset of the most common AEs (nausea, vomiting, fatigue/asthenia, anemia) and neutropenia and thrombocytopenia was < 3 months; the first event lasted a median of < 2 months, apart from fatigue/asthenia, which lasted a median of < 4 months (Table). AEs were usually managed with supportive therapy and/or dose modification; few pts discontinued. Conclusions: AEs in newly diagnosed pts with advanced OC treated with olaparib usually occurred early and were manageable, with few discontinuations. Clinical trial information: NCT01844986. [Table: see text]

e14647 Background: ONA, a type I progesterone receptor (PR) antagonist, prevents PR activation by disrupting PR dimerization and DNA binding, and inhibits tumor progression. ONA (immediate release) has efficacy comparable to other endocrine therapies in pts with metastatic breast cancer (BC). The only notable toxicity was transient elevation in liver chemistries in some pts. In 2 clinical trials, ONA ER was given to 88 cancer pts who underwent frequent liver chemistry monitoring. Methods: We pooled and reviewed all liver safety data from 2 trials. A hepatologist (PBW) reviewed all pts with either a hepatobiliary SOC AE or who experienced an elevation > ULN of any liver-related laboratory test. Results: Of 88 pts who received ONA ER for a median 8 weeks (3-51), 59% were female, median age 68 (36-89), 99% Caucasian, 28% had liver metastases (mets), 48% bone mets and 17% also took abiraterone (ABI), which has liver toxicity. 54 pts (61%) experienced any ONA ER-related AE. More AEs were seen in ABI pts (67%), those with liver mets (72%) and BC (76%).. In terms of liver-related TEAEs, overall 10% of pts had ALT and 13% AST elevations, while 20% pts with liver mets had raised ALT/AST and 29% of BC pts. Overall 15% pts had G3 TEAEs, compared to 28% pts with liver mets, mostly due to increased GGT (24%), which has unclear clinical impact. There were no discontinuations for LFT elevations. A relationship between the liver events and ONA ER was judged to be unlikely in each subject, except one. This event was detected at day 29 of treatment and consisted of a marked rise in serum GGT and alkaline phosphatase with only a moderate rise in serum ALT (peak – 262). These abnormalities improved quickly after stopping ONA but recurred on reintroduction: these events are not serious by international criteria and the pt was able to continue ONA at a lower dose for 40 weeks without recurrence Conclusions: The safety experience for ONA ER has been reassuring but must continue to be characterized. For new ONA ER studies, weekly liver chemistry monitoring is planned for the first 4 weeks with Q2W monitoring thereafter. The occasional G3 elevations in serum AST, ALT or bilirubin will prompt interruption, but re-starting treatment at a lower dose should be possible for most pts. Clinical trial information: NCT02052128 and NCT02049190.

5537Background: In ARIEL3, pts were randomized 2:1 (oral rucaparib 600 mg or placebo). Rucaparib significantly improved progression-free survival (PFS) vs placebo in all primary analysis groups (Co...

5542Background: AMH and its membrane receptor AMHRII induce regression of Mullerian ducts in the male embryo. AMHRII is constitutively expressed in ovarian granulosa tumors (GCT) and re-expressed i...

8570Background: SCLC is a deadly cancer and despite initial 80% response, almost all patients (pts) will relapse and die of this disease. Limited options exist after failure of first line, with a m...

5545Background: In ARIEL3, rucaparib significantly improved progression-free survival (PFS) vs placebo in all randomized patients, including patients with BRCA-mutant, BRCA wild-type/high-LOH (pres...

5554 Background: Longitudinal CA125 kinetics during treatment can be assessed by mathematical models. The modeled CA125 elimination parameter KELIM (with 3-4 timepoints) was an early prognostic factor in CALYPSO (Gynecol Oncol 2013). Validating the prognostic value of KELIM in phase 3 trial datasets with different 1st line treatments was warranted. Methods: Data from AGO-OVAR 9 (training set: carboplatin-paclitaxel (CP) +/- gemcitabine; n=1742); AGO-OVAR 7 (validation set: CP +/- topotecan; n=1308); and ICON 7 trials (validation set: CP +/- bevacizumab; n=1528) were analyzed. CA125 profiles were fit to nonlinear mixed effect equations, and KELIM estimated in all patients at 100 days. KELIM prognostic value was tested regarding PFS and OS against other prognostic factors (stage; pathology; grade; arms; GCIG CA125 criteria; Oza groups in ICON 7) using univariate/multivariate tests. Results: KELIM (≤ or > median 0.0598) had reproducible independent prognostic value for PFS (AGO 9: HR = 0.60 [0.53-0.69]; AGO 7: HR = 0.58 [0.40-0.83]; ICON-7: HR=0.65 [0.44-0.96]) and for OS (AGO 9: HR = 0.55 [0.47-0.64]; AGO 7: HR = 0.55 [0.35-0.86]; ICON-7: HR=0.49 [0.41-0.57]) by multivariate tests. Other significant factors for PFS & OS: stage IV in AGO7 & 9 (HR=6.0 to 8.3) and ICON 7 poor progn group (PFS HR=2.24 PFS; OS HR=2.22 [1.9-2.6]). KELIM prognostic value was independent on regimen arms (Table), maintained within ICON7 progn groups (best OS gain with bevac if poor progn & unfav KELIM), and better than GCIG CA125 (inconsistent progn value). Conclusions: The reproducible & independent early prognostic value of KELIM regarding PFS and OS is validated. Easily calculable online, it early discriminates 2 ovarian cancer populations for PFS & OS whatever treatments, and is a new reference prognostic factor. [Table: see text]

64 Background: Tumour immune response plays a critical role in progression and prognosis of EOC, however patterns of TILs and PD-L1 expression in primary and metastatic disease remain poorly described. Methods: Patients treated with neoadjuvant chemotherapy (NACT) for advanced EOC, between 2002-2014, and available sequential tumours (pre-NACT, post-NACT, or relapse) were retrospectively identified. Stromal TILs (sTILs) were evaluated according to the International TILs Working Group 2014 (Salgado 2015) on whole sections, and scored as a percentage of stromal area. Immune cell PD-L1 expression was evaluated by immunohistochemistry (E1L3N clone, Cell Signaling) in a smaller number of tumours. Cutoffs for analysis were: high sTILs ≥50%, PD-L1 positivity ≥5% membranous staining. Results: Among a total of 236 tumour samples from 150 patients (110 pre-NACT, 111 post-NACT, and 15 relapse tumours) median sTILs levels was significantly higher in metastatic tumours ( n=151) compared with primary tumours ( n=85) (median 30, IQR 10-50 vs. 15, IQR 5-30, p=0.0004). Among diagnostic samples, median sTILs level was 20 (IQR 10-45, n=85) in metastatic tumours compared with 10 (IQR 5-20, n =25) in primary tumours ( p=0064). Similarly in post-NACT samples, median sTILs level was 40 (IQR 15-60, n=51) in metastatic tumours compared with 20 (IQR 6.25-30, n=60) in primary tumours ( p=0026). Among relapse samples median sTILs level was 30 (IQR 10-50, n=15). Among all available samples ( n=97) PD-L1 positivity was detected in 33% (9/30) of primary and 50% (34/68) of metastatic tumours (Fisher’s exact test OR 2.3, 95%CI 0.94-5.4, p =0.08). Conclusions: In patients with EOC there is increased lymphocytic infiltration in both synchronous metastatic disease at diagnosis, and metachronous metastatic disease at relapse, compared with the primary tumour. This suggests increased immunogenicity as disease progresses. Furthermore, there is a trend towards upregulation of the PD-L1 immune checkpoint with disease progression.

5512Background: Lymphocytic infiltration at diagnosis is prognostic in OC, however how TILs or PDL1 expression change with NCT is unknown. Methods: We identified OC patients (pts, N = 113) treated ...

5573Background: Many HGOC are genomically unstable which likely explains their chemosensitivity. How GI changes with NACT, or relates to tumor immune infiltration and prognosis is poorly described....

5569Background: NaPi2b is a transmembrane, sodium-dependent phosphate transporter expressed in ~90% of OC. Lifa, a humanized anti-NaPi2b monoclonal antibody conjugated to the anti-mitotic agent MMA...

5508 Background: At least 50% of high-grade serous ovarian cancers (OC) may have homologous recombination deficiency (HRD). Germline BRCA1 and BRCA2 mutations (gBRCAmut) account for ~1/3. Identific...

e16546 Background: Epithelial ovarian carcinoma (EOC) is a rare disease in young women with an uncertain genetic and biological substrate. Our interest was to depict specific clinical and prognosti...

5575 Background: Most studies of OC have analysed tumors at diagnosis, little is known about the evolution of the genomic or immune landscape of OC with NC. Profiling after NC may be informative as...

5593 Background: ONA is a type I PR antagonist, which prevents PR-induced DNA transcription. Immediate release (IR) 100 mg ONA was active in multiple preclinical models and in patients (pts) with b...

TPS2604 Background: PM01183 (lurbinectedin) is a new anticancer drug that binds to the DNA minor groove and blocks trans-activated transcription, inducing formation of double-strand DNA breaks lead...

5549 Background: Vanucizumab is a bi-specific human IgG1 antibody, simultaneously blocking the complementary roles of Ang-2 and VEGF-A induced tumor angiogenesis. Both, VEGF-A and Ang-2 inhibitors ...

e16517 Background: ONA is a type I PR antagonist, which prevents PR-induced DNA transcription. ONA anti-cancer activity is documented in multiple pre-clinical models and clinical studies in pts wit...

TPS5616 Background: ONA is a type I PR antagonist, which prevents PR-induced DNA transcription. Presence of transcriptionally-activated PR (APR), seen as an aggregated subnuclear PR distribution pa...

5514 Background: The prognosis of EC is excellent and mainly driven by early stage type I EC. However, for type II or advanced EC, relapses are frequent. Genomic studies so far included mainly early stage good prognosis primary tumors. Here, we aimed to characterize genetic alterations in high risk advanced or recurrent EC, determine the rate of co-occurring mutations and evaluate concordance between primary and metastatic sites. Methods: High risk EC patients were identified from the IGR tumor bank and defined as stage III or IV, or any stage with subsequent relapse. Samples with >30% cellularity were subjected to Sanger sequencing on 79 exons from 13 genes (KRAS, NRAS, HRAS, BRAF, AKT1, PIK3CA, PIK3R1, PIK3R2, PTEN, STK11, ESR1, TP53, FGFR2). Mutation calls were confirmed by an independent analysis. Results: 75 samples from 57 patients (pts) representative of high risk EC were identified: 49% (28/57) were type II EC, 70% were stage III/IV and the remaining stage I/II pts had all relapsed. By comparison,...