Richard T. Penson's research while affiliated with Massachusetts General Hospital and other places

5592 Background: In a phase 2 study, letrozole/abemaciclib demonstrated an objective response rate (ORR) of 30% and median progression free survival (PFS) of 9.1 months in recurrent ER positive EC. While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response ( CTNNB1, KRAS,and CDKN2A mutations) and absence of response ( TP53mutations), circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. Methods: Serial plasma specimens were obtained at baseline, cycle 2 day 1 (C2D1), C3D1, C8D1, time of objective response, and at the time of progression from participants who consented for this optional collection. Samples were analyzed using the Guardant Infinity assay, which includes genotyping of > 750 genes and methylation-based tumor fraction (TF). Treatment response was assessed using the Guardant methylation-informed Molecular Response algorithm. Patients with 50% or more decrease in ctDNA levels or with absolute low ctDNA levels were defined as achieving Molecular Response (MR). Comparison of survival curves was performed using the logrank test. Results: 99/102(97%) samples from 28 patients were successfully analyzed. Three samples were excluded from analysis for not meeting sequencing quality control thresholds. Detection of ctDNA at baseline, measured via methylation-based TF, was associated with worse median PFS, (ctDNA detected (n = 18): 3.5 months vs ctDNA undetected (n = 8): 16.5 months, p = 0.006, HR = 12.5) and overall survival (OS), (ctDNA detected: 11.6 months vs ctDNA undetected: not yet reached, p = 0.008, HR = 4.7e7). Patients who achieved MR after the first or second cycle of letrozole/abemaciclib therapy exhibited better median PFS (MR(n = 13): 12.8 vs not-MR(n = 10): 3.5 months, p < 0.001, HR = 0.1) and were more likely to demonstrate clinical benefit (objective response and/or progression free survival for ≥6 months) from this regimen (MR: 84.6% vs not-MR: 10.0%, p < 0.001, odds ratio (OR) = 49.5). ctDNA analysis of post-progression specimens identified several acquired genomic alterations associated with resistance to combined aromatase/CDK4&6 inhibitor therapy, such as ESR1 mutations/amplification, RB1 mutations, ERBB2 amplification/mutations and CCNE1 amplification. Of note, 2 of the 3 patients with mismatch repair deficient (dMMR) ECs acquired ESR1 mutations at the time of progression; both patients had exhibited durable objective responses to therapy. Conclusions: Baseline and on-treatment ctDNA dynamics may provide an early indication of long-term outcomes and benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify genomic alterations of acquired resistance (such as ESR1, RB1, CCNE1,and ERBB2 alterations) that may guide selection of subsequent therapy.

5571 Background: Olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), has shown efficacy as monotherapy for the treatment of BRCA mutated (BRCAm) advanced ovarian cancer (AOC) and in combination with bevacizumab for Homologous Recombination Deficient (HRD+) AOC. This study describes real-world (RW) characteristics, testing and treatment patterns in patients (pts) with AOC, including outcomes with olaparib first-line maintenance (1LM) therapy. Methods: A retrospective observational study utilizing the electronic health record-derived de-identified US-based Flatiron Health database was performed including women aged ≥18 y at AOC diagnosis (Jul 2018–Dec 2022) with ≥1 clinical visit. Pts were followed from diagnosis until Aug 31, 2023, cessation of dataset coverage, or death, whichever occurred first. Biomarker testing was defined as evidence of a test for BRCAm or HRD (inclusive of BRCAm). Estimated RW time to first subsequent therapy or death (TFST) and time to treatment discontinuation or death (TTD) are reported. Results: Demographic and clinical characteristics are shown in the Table. Of 1503 pts included, 80.8% (n=1214) were BRCAm tested and 36.3% (n=546) were HRD (inclusive of BRCAm) tested. Among pts who were either BRCAm or HRD tested (n=1220), 58.0% (n=708) were tested between AOC diagnosis and initiation of 1LM therapy. No 1LM therapy was recorded in 61.9% (n=931/1503) of pts. In both BRCAm and HRD+ pts, olaparib, either as monotherapy (44.5% [n=69/155] and 33.6% [n=100/298], respectively) or in addition to bevacizumab (7.1% [n=11/155] and 9.4% [n=28/298], respectively), was the most frequently used PARPi for 1LM therapy (Table). Median (95% CI) TFST and TTD was 44.7 (27.0, NA) and 22.7 (17.0, 47.0) mos, respectively in BRCAm pts receiving olaparib 1LM (n=69), and 29.1 (22.1, NA) and 22.1 (13.1, NA) mos, respectively in HRD+ pts receiving olaparib + bevacizumab 1LM (n=28). Conclusions: While most pts received BRCAm testing, a majority did not receive HRD (inclusive of BRCAm) testing. A sizeable proportion of pts with actionable biomarker results did not receive PARPi as 1LM therapy highlighting the need for education on the importance of genetic testing to guide AOC treatment. Time-to-event outcomes were comparable with those from the SOLO1 and PAOLA-1 clinical trials, thus supporting the real-world effectiveness of olaparib. [Table: see text]

PURPOSE The multicenter, open-label, randomized phase 2 NCI-9944 study ( NCT02595892 ) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.

Purpose: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. Patients and methods: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pre-treatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. Results: 91 patients initiated treatment, 38 in dose escalation. 58% had ³3 prior therapies. 15 patients (17%) had colorectal cancer (CRC), 19 (11%) pancreatic, 15 (167%) NSCLC, and 32 (35%) GYN cancers. The recommended phase 2 dose (RP2D) was established as trametinib 2mg daily days 1-14 and navitoclax 250mg daily days 1-28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8/49 (16.3%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In GYN patients at the RP2D, 7/21 (33.3%) achieved a PR and median duration of response 8.2 months. No PRs occurred in CRC, NSCLC, or pancreatic patients. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. Conclusions: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

Simple Summary Poly (ADP-ribose) polymerase (PARP) inhibitors have become an essential part of the anticancer armamentarium in ovarian cancer. As maintenence therapy they have been shown to extend survival, and may improve the chance of cure in first line. However, later line treatmewnt is associated with a negative impact on survivaL and limited their use outside trials to first line and secondline in patients with a BRCA mutated cancer. Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors have become an established part of the anticancer armamentarium. Discovered in the 1980s, PARP inhibitors (PARPis) were initially developed to exploit the presence of BRCA mutations, which disrupt the homologous recombination repair of deoxyribonucleic acid (DNA) via synthetic lethality, an intrinsic vulnerability caused by the cell’s dependence on other DNA repair mechanisms for which PARP is an essential contributor. PARPi use expanded with the demonstration of clinical benefit when other mechanisms of high-fidelity DNA damage response were present in cancer cells called homologous repair deficiency (HRD). Recently, new data have resulted in the voluntary withdrawal of later-line treatment indications for all the available PARPis used in ovarian cancer because of a negative impact on overall survival (OS). PARPi switch maintenance to consolidate a response to platinum-based therapy is recommended for earlier treatment lines to have the greatest impact on the chance of cure and length of survival. This article reviews the clinical utility of PARPis and how to integrate them into best practices.

Purpose Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). Patients and Methods In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). Results The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1–97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5–43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2–86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. Conclusions Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.

PURPOSE To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC). METHODS This placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT03398655 ) randomly assigned patients with PROC 1:1 to receive intravenous ofra-vec every 8 weeks with once a week IV paclitaxel or placebo with paclitaxel until disease progression. The dual primary end points were overall survival (OS) and progression-free survival (PFS) as assessed by Blinded Independent Central Review. RESULTS Between December 2017 and March 2022, 409 patients were randomly assigned. The median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29; P = .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .8440). Objective response rates (ORRs) per RECIST 1.1 were similar in both arms: 28.9% with ofra-vec versus 29.6% with control. In both treatment arms, response to CA-125 was a substantial prognostic factor for both PFS and OS. In the ofra-vec arm, the HR in CA-125 responders compared with that in nonresponders for PFS was 0.2428 (CI, 0.1642 to 0.3588), and for OS, the HR was 0.3343 (CI, 0.2134 to 0.5238). Safety profile was characterized by common transient flu–like symptoms such as fever and chills. CONCLUSION The addition of ofra-vec to paclitaxel did not improve PFS or OS. The PFS and ORR in the control arm exceeded the results that were anticipated on the basis of the AURELIA chemotherapy control arm. CA-125 response was a substantial prognostic biomarker for PFS and OS in patients with PROC treated with paclitaxel.

Introduction/Background BACKGROUND: While an increasing number of patients with BRCA-mutated ovarian cancer receive first-line maintenance PARP inhibitors, there is still a group of patients who are PARPi naïve for various reasons, and who relapse. A subgroup analysis of the SOLO2 trial of maintenance olaparib provides information about the outcome of patients receiving maintenance olaparib after a response to platinum-based therapy for first recurrence. Methodology In SOLO2/ENGOT-Ov21 patients with high grade ovarian cancer and a BRCA-mutation were randomised 2:1 to receive olaparib or placebo after a response to platinum-based therapy. Out of the 295 patients enrolled in the trial, 172 had one prior line of chemotherapy (110 olaparib; 62 placebo) prior to recurrence. Treatment with olaparib or placebo continued until progression, toxicity, or lack of further clinical benefit. An exploratory analysis of progression-free survival (PFS) and overall survival (OS) was performed as well as the long-term toxicity. Results In the 172 second-line patients, a complete response to chemotherapy was seen in 52%, and 70% had a platinum-free interval of more than 12 months before randomisation. The median PFS was 24.2 (16.4–33.2) versus 5.7 (95%CI 5.3–8.2) months in the olaparib and placebo arms respectively (HR 0.46, 95%CI 0.32–0.66). With 58% data maturity, OS favoured olaparib (median 56.3 months, 95%CI 43.9–67.4) over placebo (37.4 months, 95%CI 27.1–60.3) (HR 0.79, 95%CI 0.53–1.19). Conclusion For patients with a BRCA mutation who did not have the opportunity to receive a PARPi in first-line, this exploratory analysis of SOLO2 in patients with first recurrence showed that maintenance olaparib following a response to chemotherapy leads to a clinically meaningful survival benefit. These results support the recommended use of olaparib in this patient subgroup. Disclosures Sponsored by AstraZeneca. Led by GINECO Group