bluuebunny/crossref_metadata_2025 huggingface dataset:
Biallelic loss of TP53, PTEN, and RB1 in association to aggressive clinical features and poor outcomes in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Maurice-Dror Corinne , Fonseca Nicolette , Herberts Cameron , Kwan Edmond Michael , Kollmannsberger Catarina , Tu Wilson , Khalaf Daniel Joseph , Annala Matti , Schönlau Elena , Bernales Cecily Q. , Donnellan Gráinne , Vergidis Joanna , Noonan Krista , Finch Daygen L. , Zulfiqar Muhammad , Stacy Miller , Wyatt Alexander William , Chi Kim N.
Published: June 2022

5055

Background: Deleterious alterations in tumor suppressor genes (TSGs) TP53, RB1, and PTEN are potential markers of small cell neuroendocrine prostate cancer (SCNP), and androgen receptor pathway inhibitor (ARPI) resistance. We examined the outcomes and clinical features of mCRPC patients (pts) harboring biallelic loss in 0, 1, 2 or all 3 TSGs. Methods: We identified 210 consecutive mCRPC pts providing ≥1 plasma cell-free DNA sample with ≥20% circulating tumor DNA fraction (ctDNA%) during their mCRPC disease course. ctDNA% ≥20% enabled sensitive characterization of biallelic TSG loss (including by homozygous deletions and mutation plus somatic loss-of-heterozygosity; LOH). Patient records were reviewed for baseline characteristics, SCNP histology, and presence of liver metastases. We investigated associations between TSG loss and the following clinical outcomes: PSA response (PSA decline ≥50% (PSA50 RR)), progression free survival (PFS) on 1L therapy, and overall survival (OS) from 1L therapy. Results: Median follow-up was 16.5 months (range: 0.4-112.4) and OS event rate was 95%. Median age at 1L mCRPC was 71 years (range: 48-98). Most pts were ECOG PS 0-1 (79%) and 13% had liver metastases. 91% received ARPI for 1L mCRPC and 7% received ARPI for castration-sensitive disease. TP53 was primarily inactivated by somatic mutation plus LOH (90%), whereas RB1 (71%) and PTEN (86%) were more commonly inactivated by homozygous deletions. Compared to pts without evidence of biallelic TSG loss, pts with loss of 3 TSGs were significantly enriched for de-novo M1 disease (86 vs. 60%, p=0.05) and liver metastases (28.5 vs. 6.8%, p<0.05). Ten pts (4.7%) had histologically confirmed SCNP and provided ctDNA at time of SCNP diagnosis. Of these, 7 (70%) had biallelic loss of ≥2 TSGs. For all pts receiving 1L therapy, loss of ≥1 TSG(s) was associated with decreased OS (HR: 1.86, 95% CI: 1.40-2.48, p<0.01) and PFS (HR:1.74, 95% CI 1.29-2.34, p<0.01) compared to pts with no biallelic TSG loss. Furthermore, a cumulative increase in the number of TSGs lost was associated with an incremental reduction in OS and PFS (Table). Conclusions: In a cohort enriched for poor prognosis (i.e. high ctDNA%), cumulative loss of TSGs is associated with aggressive disease features and poor clinical outcomes. These patients may benefit from alternative treatment intensification strategies. [Table: see text]
A pilot trial of neoantigen DNA vaccine in combination with nivolumab/ipilimumab and prostvac in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Shah Koral , Ganapathy Aravinda , Borkowski Ariel , Shah Nakul , Bansal Dhruv , Beck Rachel , Knoche Eric Marshall , Picus Joel , Reimers Melissa Andrea , Roth Bruce J. , Gulley James L. , Schreiber Robert , Pachynski Russell Kent
Published: June 2022

5068

Background: Treatment with immune checkpoint blockade (ICB) alone results in suboptimal response rates in prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self-antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens have been correlated with favorable clinical outcomes. Thus, we hypothesized that the combination of shared antigen and neoantigen vaccines with dual ICB will induce robust immune responses and improve clinical outcomes. Methods: This Phase I clinical trial (NCT03532217) enrolled patients from 2018-2021. Eligible patients had histologically confirmed high risk mHSPC, must have completed a course of docetaxel and received continuous androgen deprivation therapy. Patients were treated with Prostvac-VF in combination with ipilimumab/nivolumab within 60 days of the last docetaxel dose. Then, patients were continued on monthly nivolumab with their personalized neoantigen vaccine administered via intramuscular electroporation. The primary objectives of this study were to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure free survival, milestone overall survival (OS), PSA responses, and radiographic progression free survival. Results: Nineteen patients were enrolled and treated on trial, and feasibility was shown with 15 (79%) receiving neoantigen vaccines. Four patients did not receive neoantigen vaccines (2 for progressive disease, 2 for ICB toxicity). Treatment was well-tolerated with only 2 (2.4%) grade 3 treatment related adverse events (TRAEs) of colitis, and no grade 4+ TRAEs. The common grade 1-2 TRAEs were diarrhea (10%), injection site reactions (10%), rash (7.4%), and fatigue (6%). Median follow-up to date is 22.6 (11.3-39.6) months, with median OS not yet reached and 2 year milestone OS of 75%. Six (31.5%) patients had PSA progression per PCWG2 criteria while on treatment, with the median time to PSA progression not yet reached for the total population. Increases in activation/co-stimulatory/co-inhibitory seen after treatment with Prostvac/ICB, suggest immune priming. Sample collection is complete and immune correlative analyses are ongoing. Final safety/tolerability and preliminary correlative and clinical outcomes will be reported. Conclusions: This is the first clinical trial evaluating the use of personalized neoantigen vaccines in a combination immunotherapeutic approach in mHSPC patients. Clinical trial information: NCT03532217.
Historical early treatment effects of adjuvant endocrine therapy for breast cancer in high-risk subgroups: Reanalysis of BIG 1-98, SOFT and TEXT.
Authors: Regan Meredith M. , Niman Samuel M. , Fleming Gini F. , Walley Barbara , Viale Giuseppe , Thurlimann Beat J. K. , Loi Sherene , Colleoni Marco , Pagani Olivia , Francis Prudence A.
Published: June 2022

508

Background: Clinical trials testing adjuvant endocrine therapy (ET) have not historically limited enrollment to patients with clinically high-risk breast cancer (BC), nor estimated treatment (trt) effects prior to 5 yrs. In light of recent trial results for adjuvant CDK4/6 inhibitors, we estimated early relative and absolute trt effects of aromatase inhibitor (AI) vs tamoxifen (T), with ovarian suppression (OFS) if premenopausal, in high risk subgroups. Methods: From pts enrolled in adjuvant phase 3 randomized clinical trials BIG 1-98 (postmenopausal, 5yr AI v T), TEXT (5yr AI+OFS v T+OFS) and SOFT (5yr AI+OFS v T+OFS v T), we identified subgroups with HR+/HER2- BC and high risk features (≥4 pLN; or 1-3 pLN with grade 3, pT≥5 cm and/or Ki-67≥20% [retrospectively centrally assessed]). TEXT randomized at start of adjuvant trt; BIG 1-98 and SOFT after chemotherapy. Disease-free survival (DFS) was defined from randomization to invasive recurrence at local, regional, distant or contralateral breast, second non-breast malignancy or death. We estimated trt effects as differences in 2, 3 and 5yr DFS Kaplan-Meier estimates (KM diffs at t yrs) and hazard ratios over time intervals of 0-2, 0-3 and 0-5 yrs (HRs over 0 to t yrs) to approximate the maturity of trial results with increasing follow-up. Results: The high-risk HR+/HER2- subgroups were 695/4922, 707/2660 and 526/3047 pts in BIG 1-98, TEXT and SOFT with 202, 122, 142 DFS events observed by 5 yrs since randomization. 60%, 46% and 44% of pts had ≥4 pLNs; 42%, 90% and 92% had chemotherapy. The table summarizes results. Conclusions: In re-analysis of clinical high risk HR+/HER2- subgroups of 3 trials each ̃700 pts, 5 yrs AI vs T had similar magnitude of early trt effects after 2-3 yrs follow-up of all pts vs trt effects observed after 27 mos median follow-up in monarchE trial (HR=0.70; KM diffs 2.7% at 2 yrs, 5.4% at 3 yrs; n=5637). Relative and absolute trt effects sometimes diminished when estimated over 5 yrs rather than over 2 yrs, but meaningful absolute differences remained at 5 yrs in contrast to Penelope-B trial results. Design and interpretation of high risk HR+/HER2- early BC trials may depend on timing of randomization and selection of backbone adjuvant trts; follow-up >5 yrs must remain standard. [Table: see text]
Salvage radiotherapy guided by functional imaging for macroscopic local recurrence following radical prostatectomy: A multicentric retrospective study.
Authors: Benziane Ouaritini Nicolas , Zilli Thomas , Ingrosso Gianluca , Pasquier David , renard Penna Raphaelle , Ferrari Victoria , Achard Verane , Pasquier Corentin , Perennec Tanguy , Di Staso Mario , Mihoci Inga , Trippa Fabio , Francolini Giulio , Meyer Emmanuel , Schick Ulrike , Cosset Jean Marc , Martin Etienne , Supiot Stephane , Latorzeff Igor , Sargos Paul
Published: June 2022

5089

Background: For prostate cancer (Pca), salvage radiotherapy (sRT) with or without androgen deprivation therapy (ADT) is currently the only curative treatment option in case of post-radical prostatectomy (RP) biochemical relapse (BR). Functional imaging techniques have shown that macroscopic recurrence (MR) in the prostate bed (PB) are frequent. In this study, we aimed to assess efficacy and safety of sRT in patients with MR inside the PB proven by functional imaging. Methods: A multicenter retrospective study was conducted in 16 European centers. Patients were included if they displayed BR after RP for Pca, with MR only in the PB proven by functional imaging. All patients had to be eligible for sRT. The overall population was divided along 4 groups according to the delivered treatment: dose escalation on MR (A), dose escalation on PB (B), double dose escalation MR+PB (C), no dose escalation (D). The primary endpoint was progression-free survival (PFS). Secondary outcomes included the metastasis-free survival (MFS), biochemical PFS (bPFS) and overall survival (OS). Grade ≥2 genito-urinary (GU) and gastro-intestinal (GI) acute and late toxicities were collected. Results: Between January 2000 and December 2019, 363 patients with isolated MR after RP for Pca were treated by sRT. The median pre-sRT PSA level was 0.63ng/mL (range, 0.2-23.6). At the time of BR, 266 (73%) patients presented MR in the PB proven by magnetic resonance imaging, and 110 (30%) by positron emission tomography. The median follow-up was 53.6 months (range, 47.52; 58.32). The 5-year PFS and MFS were 70% (95%CI [63.8-75.4]) and 83.7% (95%CI [78.4-87.8]), respectively. Grade ≥2 GU and GI late toxicities were found in 43 (12%) and 11 (3%) patients, respectively. A 5-year PFS benefit was highlighted for groups A, B and C (313 patients) when the MR dose was ≥72Gy: 72,8% (95%CI 64.6-79.4) versus 60.3% (95%CI 48,4-70,3), p = 0.03. Conclusions: In a modern series integrating functional imaging data, we confirmed that sRT is effective in the event of MR inside the PB, with an acceptable toxicity profile. In addition, with the help of functional imaging, we found that dose escalated ≥ 72 Gy on the MR had a significant impact on PFS. Prospective data should further investigate the correlation between MR-targeted dose escalation and PFS.
Racial/ethnic disparities in locoregional recurrence in hormone-receptor positive node-negative breast cancer patients enrolled in the TAILORx trial.
Authors: Kantor Olga , King Tari A. , Freedman Rachel A. , Mayer Erica L. , Chavez Mac Gregor Mariana , Korde Larissa A. , Sparano Joseph A. , Mittendorf Elizabeth A.
Published: June 2022

515

Background: Whether racial/ethnic disparities in locoregional recurrence (LRR) exist in patients (pts) with similar access to care treated on clinical trials is uncertain. We examined racial/ethnic differences in LRR in hormone-receptor positive HER2-negative (HR+HER2-) node-negative pts enrolled in the TAILORx trial. Methods: 10,273 pts age 18-75 were enrolled in TAILORx, which assigned pts with an OncotypeDx Recurrence Score (RS) <11 to endocrine therapy (ET) alone, those with RS >25 to chemotherapy + ET (CET), and randomized pts with RS 11-25 to ET or CET. Pts with unknown race/ethnicity (n=323) or incomplete treatment adherence information (n=1,168) were excluded from this analysis. Race/ethnicity was self-reported. LRR was defined as ipsilateral invasive in-breast, chest wall, or regional nodal recurrence without distant recurrence. Kaplan-Meier curves were used to estimate 8-year LRR. Cox proportional hazards analysis adjusted for clinical and treatment factors was used to determine factors associated with LRR. Results: 8,782 pts with T1-2N0 HR+HER2- breast cancer were included. Race/ethnicity was non-Hispanic White (NHW) in 6,932 (78.9%), non-Hispanic Black (NHB) in 629 (7.2%), Hispanic in 818 (9.3%), and Asian in 403 (4.6%). Treatment adherence was high across groups over time, with a 9.1% crossover in treatment arms. Average duration of ET was 63.8 +/- 0.3 months. Radiation therapy was planned in 96.0% of pts after breast conservation and 12.7% after mastectomy. At a median follow-up of 8 years, LRR rates were 1.9% in NHW, 4.2% in in NHB, 3.2% in Hispanic, and 3.9% in Asian pts (p<0.01). LRR rates broken down by RS are shown in the Table. On adjusted analyses, NHB and Asian (vs. NHW) pts were more likely to have LRR (HR 1.94 for NHB, HR 2.04 for Asian, p<0.05 for both). Additional statistically significant factors associated with LRR included age <50 (HR 1.85), T2 tumors (HR 1.43), higher grade (HR 2.30 for grade 3), and high RS (HR 3.13 for RS>25). Treatment receipt (chemotherapy, ET duration, and radiation) was not associated with LRR in this population. Conclusions: Racial/ethnic differences in LRR were seen in T1-2N0 HR+HER2- breast cancer pts enrolled in the TAILORx trial despite high rates of treatment adherence in this clinical trial population, with highest LRR rates in NHB and Asian pts. Further study in needed to understand racial/ethnic patterns in LRR by breast cancer subtype and if failure to rescue after LRR may contribute to differences in breast cancer mortality.[Table: see text]
Adjuvant abemaciclib for high-risk early breast cancer (EBC): Factors increasing the rate of treatment discontinuations in monarchE.
Authors: Tolaney Sara M. , Johnston Stephen R.D. , Wei Ran , Andre Valerie AM , Shahir Ashwin , Harbeck Nadia , Martin Miguel
Published: June 2022

527

Background: Adjuvant abemaciclib plus endocrine therapy (ET) demonstrated clinically meaningful improvement in reducing the risk of recurrence in patients (pts) with HR+, HER2– high risk EBC. In monarchE, 25.6% pts discontinued abemaciclib before completing the 2-year treatment period due to reasons other than recurrence. This exploratory analysis evaluates the impact of baseline factors on time to discontinuation for abemaciclib-treated patients with an aim to identify pts at higher risk of discontinuation. Methods: Time to discontinuation(TTD) was defined as time from first dose to the discontinuation of abemaciclib or all treatment due to reasons other than recurrence. These exploratory analyses evaluated the association between TTD and baseline demographics, disease characteristics, and the extent of pre-existing medical comorbidities. Factors with p-value <0.05 in the univariate Cox model were considered as potentially associated with TTD and then fitted into a multivariate Cox model with stepwise variable selection, with entry and retaining p-value threshold of 0.05. Discontinuation rates at selected timepoints (6-month, 12-month, 18-month, 24-month) within each subgroup were estimated using the Kaplan-Meier method. Results: The following variables were significantly associated with higher risk of discontinuation in the multivariate model: Age ≥65 yr, enrolled in North America or EU, ECOG PS=1, post-menopausal, 1-3 positive nodes, or 4 or more pre-existing comorbidities. The majority of discontinuations occurred within the first 6 months of the treatment period; thus, this timepoint was selected to estimate discontinuation rates for factors independently associated with TTD (Table). Complete results on discontinuation rates at other timepoints will be reported in the presentation. Conclusions: This exploratory analysis identified several factors associated with a greater risk of discontinuation. These results illustrate the importance of close monitoring and dose adjustments early on, particularly for patients with an increased risk of discontinuation prior to completing the 2-yr treatment period of abemaciclib. Clinical trial information: NCT03155997. [Table: see text]
Breast density reduction as a predictor for prognosis in premenopausal women with hormone receptor–positive breast cancer: A retrospective analysis of the ASTRRA study.
Authors: Bae Soong June , Kim Hyun-Ah , Ryu Jai Min , Park Seho , Lee Eun-Gyeong , Im Seock-Ah , Jung Yongsik , Park Min Ho , Park Kyong Hwa , Kwang Su Hwan , Park Eunhwa , Kim Sung Yong , Lee Min Hyuk , Kim Lee Su , Lee Anbok , Noh Woo Chul , Ahn Sei-Hyun , Kim Seonok , Kim Hee Jeong , Jeong Joon
Published: June 2022

531

Background: While the relationship between mammographic breast density (MD) decline and anti-hormone therapy efficacy has been reported in estrogen-receptor (ER)-positive breast cancer, it is still unclear in premenopausal women and in the case of adding ovarian function suppression (OFS) to anti-hormone therapy. We aimed to investigate the MD reduction (MDR) rate and impact of MDR on prognosis stratified by treatment from the updated result of the ASTRRA trial. Methods: ASTRRA trial, a randomized phase 3 study, showed that adding ovarian function suppression (OFS) to tamoxifen (TAM) improved survival in premenopausal women with ER+ breast cancer after chemotherapy. We updated survival outcomes with a median follow-up of 108 months. We assessed mammography taken before treatment and the follow-up mammography taken annually for up to five years after initiation of treatment. MD was classified into four categories based on the Breast Imaging Reporting and Data System. MDR positivity was defined as a downgrade in MD among follow-up mammography up to two years after randomization, with the pretreatment MD grade as a reference. Results: Among the 1,293 patients from ASTRRA trial, we successfully evaluated MDR in 947 patients, of which 796 (83.4%) belong to high MD (grade C or D). The patient characteristics were similar between the entire ASTRRA trial and the subgroup with available MDR. There was no difference in MDR-positive rate between two treatment groups (106 of 477 [22.2%] in TAM-only group vs. 87 of 470 [18.5%] in TAM + OFS group, P =.156). MDR-positivity was significantly associated with better disease-free survival (DFS) in TAM + OFS group (estimated 8-year DFS: 92.9% in MDR-positive vs. 82.2% in MDR-negative, P =.013), but did not in TAM-only group (estimated 8-year DFS: 80.3% in MDR-positive vs. 80.2% in MDR-negative, P =.927; Pinteraction =.025). Simialr trends were observed in terms of recurrence-free survival, distant metastasis-free survival (DMFS), locoregional-free survival, and overall survival. In addition, MDR-positivity was an independent factor for favorable DFS (adjusted hazard ratio [HR], 0.37; 95% CI, 0.16 to 0.86; P =.021) and DMFS (adjusted HR, 0.35; 95% CI, 0.13 to 0.98; P =.045) in TAM + OFS group. Conclusions: Although the proportion of patients with MDR-positive was comparable between the two treatment groups, MDR-positive was independently associated with favorable outcomes only in TAM + OFS group. Future work is warranted to verify the mechanism by which the association between MDR and clinical benefit differs according to the treatment group. Clinical trial information: NCT00912548.
Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.
Authors: Oaknin Ana , Pothuri Bhavana , Gilbert Lucy , Sabatier Renaud , Ghamande SharadA. , Gravina Adriano , Calvo Emiliano , Banerjee SusanaN. , Miller Rowan , Pikiel Joanna , Mirza MansoorRaza , Duan Tao , Zildjian Sybil , Zografos Eleftherios , Veneris JenniferLynnTaylor , Tinker Anna
Published: June 2022

5509

Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the U.S. as a monotherapy in patients (pts) with dMMR AR EC that has progressed on or after treatment with a platinum-containing regimen or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; and in the E.U. as a monotherapy in pts with dMMR/MSI-H AR EC that has progressed on or after treatment with a platinum-containing regimen. Here, we report on efficacy and safety in the 2 expansion cohorts of the GARNET trial that enrolled pts with EC. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or cohort A2 (MMRp/MSS EC) based on local assessment. Pts received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1,000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints are ORR and DOR by blinded independent central review using RECIST v1.1. Results: For this third interim analysis, 153 dMMR/MSI-H and 161 MMRp/MSS pts were enrolled and dosed. Of these, 143 dMMR/MSI-H and 156 MMRp/MSS pts had measurable disease at baseline and ≥ 6 mo of follow-up and were included in the efficacy-evaluable population. ORRs were 45.5% (dMMR/MSI-H) and 15.4% (MMRp/MSS; Table). Median (m) DORs were not reached (NR; dMMR/MSI-H) and 19.4 mo (MMRp/MSS). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 35.8%, 31.3%, and 29.4% in MMRp/MSS EC, respectively. mOS was NR (dMMR/MSI-H) and 16.9 mo (MMRp/MSS). Overall, 27 pts (8.6%) discontinued treatment because of a treatment-related adverse event (TRAE; 13 dMMR/MSI-H, 14 MMRp/MSS). The majority of TRAEs were grade 1 or 2. The most common any-grade TRAEs were fatigue (56; 17.8%), diarrhea (46; 14.6%), and nausea (43; 13.7%). No deaths were attributed to dostarlimab in the EC cohorts. Hypothyroidism (12; 8%) was the most common any-grade immune-related TRAE. Conclusions: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with better outcomes: a higher response rate and longer PFS and OS. Safety was consistent with other PD-1 antibodies. Clinical trial information: NCT02715284. [Table: see text]
IGNITE: A phase II signal-seeking trial of adavosertib targeting recurrent high-grade, serous ovarian cancer with cyclin E1 overexpression with and without gene amplification.
Authors: Au-Yeung George , Bressel Mathias , Prall Owen , Surace Daniela , Andrews John , Mongta Sally , Lee Yeh Chen , Gao Bo , Meniawy Tarek , Baron-Hay Sally E. , Black Allison Jane , Kichenadasse Ganessan , Ananda Sumitra , Fox Peter , Bowtell David , Mileshkin Linda R.
Published: June 2022

5515

Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC with cyclin E1 over-expression, with and without gene amplification. Methods: IGNITE is a multicentre, phase 2 trial with 2 cohorts of women with recurrent platinum resistant HGSC. Tumors were assessed for cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients were assigned to Cohort 1 if tumors were cyclin E1 over-expressed (H-score>50) and amplified (≥8 copies), and Cohort 2 if tumors were overexpressed and nonamplified. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was investigator assessed clinical benefit (CB) defined as absence of progression for ≥ 18 weeks. Here we present the 18-week response data for the first 32 patients treated from Cohort 2, with a data cut-off of August 2021. Results: Between Jan-2020 and May-2021, 32 patients were accrued to Cohort 2. Median age was 62 years (range 42-77) and 84% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 120 and 28 patients (88%) had measurable disease by RECIST. Median number of cycles commenced was 8 (range 1-19). Overall response rate (ORR) was 53% and CB rate was 61% for all evaluable patients. Seventeen patients (53%) required a dose reduction, most commonly for neutropenia or fatigue. Seventeen patients experienced ≥Grade 3 treatment related adverse event, and 4 patients (15%) discontinued due to toxicity. Conclusions: The efficacy results in a biomarker-selected cohort of patients are promising with a higher response rate than reported in previous studies of adavosertib in unselected women with recurrent HGSC. Duration of response and progression free survival data will be presented as data matures. Clinical trial information: ACTRN12619001185156P. [Table: see text]
A phase 1 trial of the PARP inhibitor fuzuloparib in combination with the anti-angiogenic apatinib in recurrent ovarian or triple-negative breast cancer.
Authors: Li Huiping , Zhang Jiayang , Yin Rutie , Song Nan , Zhang Youzhong , Zhang Yu , Zhang Keqiang , Pan Hongming , Wang Ke , Lou Ge , Guiling Li , Zhang Ben , Wang Quanren , Gao Yunong
Published: June 2022

5539

Background: The combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor has demonstrated improved clinical outcomes as treatment/maintenance treatment in gynecological cancers. Here we aimed to characterize the safety profile and recommended phase 2 dose (RP2D) of the combination of fuzuloparib (formerly fluzoparib), a PARP inhibitor, and apatinib, a VEGFR inhibitor in recurrent ovarian cancer (OC) or triple-negative breast cancer (TNBC). Methods: This was a dose-escalation and PK-expansion phase 1 trial conducted in China. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer or metastatic TNBC were eligible. No prior PARP/VEGFR inhibitors were allowed. The study used a standard 3+3 dose-escalation design, with additional patients (a total of 8-12 patients per dose level) enrolled for PK assessment. Patients received orally a single dose of fluzoparib on D1 and apatinib on D4, followed by continuous dosing of fluzoparib (bid) plus apatinib (qd) starting on D8. Endpoints were RP2D, safety, PK, and anti-tumor activity. Results: Between 03/17/2017 and 03/02/2021, 52 patients (30 OC, 22 TNBC) were enrolled to 7 dose levels (up to fuzuloparib 100 mg plus apatinib 500 mg). A total of 2 DLTs occurred: grade 4 decreased white blood cell count (WBC)/febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and grade 4 thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). No maximum tolerated dose was reached. The most common treatment-related grade ≥3 toxicities included hypertension, anemia/decreased hemoglobin, thrombocytopenia, and decreased WBC. In PK analysis, steady-state plasma concentrations of apatinib was decreased when combined with fuzuloparib, as compared with apatinib alone. Higher dose of apatinib in combination with fuzuloparib 100 mg was associated with higher exposure and improved clinical activity. The ORR was 44% (95% CI, 32-58; OC, 60% [95% CI, 42-75]; TNBC, 23% [95% CI, 10-43]) across all dose levels and 62.5% (95% CI, 31-86) at fuzuloparib 100 mg plus apatinib 500 mg (all OC), which was determined to be the RP2D. Conclusions: Fuzuloparib plus apatinib has acceptable safety in patients with recurrent ovarian cancer and triple-negative breast cancer. With the promising clinical activity observed in ovarian cancer, this combination is warranted to be further explored as a potential alternative to chemotherapy. Clinical trial information: NCT03075462.
The effect of advances in epithelial ovarian cancer treatment on population mortality.
Authors: Wang Aifen , Ye Qing , Lv Jinghuan , Hu Weidong , Feng Ninghan , Hou Shunyu
Published: June 2022

5540

Background: Epithelial ovarian carcinoma is the most common and progressive subtype of ovarian cancer. Mortality trends based on race remains unclear. Methods: SEER was used to assess epithelial ovarian cancer mortality and relevant deaths from epithelial ovarian cancer to incident cases. Population-level mortality trends were evaluated according to specific causes. In addition, epithelial ovarian cancer incidence and survival was assessed according to calendar year and race. We applied Joinpoint software to evaluate trends in incidence or incidence-based mortality. Results: Age-adjusted incidence of white patients was the highest, followed by Asians and Black patients. Incidence-based mortality of Asian patients was the lowest among all patients, followed by White and Black patients. Incidence-based mortality of all causes of death of epithelial ovarian cancer increased sharply by 65.09% annually from 2000 through 2002, then rose gradually by 9.45% annually from 2002 through 2005, and then increased more slowly annually from 2005 through 2018. Other causes of death of incidence-based mortality displayed similar trends. However, incidence-based mortality of specific ovarian epithelial cancer deaths displayed an annual decrease of 0.08% from 2005 through 2018, following a sharp annual increase of 65.68% from 2000 through 2002 and 6.55% from 2002 through 2005. White patients with epithelial ovarian cancer showed the highest 2-year relative survival, followed by Asians, Black patients and Native Americans, with all patients showing an improved survival rate. Among White patients with epithelial ovarian cancer, incidence increased annually by 1.98% from 2000 through 2011 and then flattened out to an annual increase of 0.03%. Incidence-based mortality of White patients increased sharply by 56.70% annually from 2000 through 2002, then increased slowly by 7.90% annually from 2002 through 2005, and 2.00% annually from 2005 through 2018. Among Asian patients with epithelial ovarian cancer, incidence increased at an annual rate of 2.39% from 2000 through 2018. Incidence-based mortality of Asian patients increased steeply by 78.70% annually from 2000 through 2002, then slowed down to an annual rate of 2.50% from 2002 through 2018. Among Black patients with epithelial ovarian cancer, incidence increased annually by 10.83% from 2000 through 2002 and 2.43% from 2006 through 2016 and declined annually by 0.82% from 2002 through 2006 and by 1.82% from 2016 through 2018. Incidence-based mortality of Black patients displayed a sharp annual increase of 63.70% from 2000 through 2002, then slowed to an annual rate of 1.90% from 2002 through 2018. Conclusions: Incidence-based mortality of specific ovarian epithelial cancer death decreased annually from 2005 through 2018. These results may be related to treatment advances of epithelial ovarian carcinoma, particularly surgical strategy and chemotherapy.
Efficacy of niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer in phase 3 PRIME study: A subgroup analysis by response to first-line platinum-based chemotherapy.
Authors: Yin Rutie , Li Ning , Wu Lingying , Wang Jing , Zhu Jianqing , Pan Lingya , Kong Beihua , Zheng Hong , Liu Jihong , Wu Xiaohua , Wang Li , Huang Yi , Wang Ke , Zou Dongling , Zhao Hongqin , Wang Chunyan , Lu Weiguo , Zhen Xiaoa , Hang Wenzhao , Hou Jianmei
Published: June 2022

5551

Background: In PRIME (NCT03709316), niraparib significantly reduced the risk of disease progression or death versus placebo (PBO) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.34–0.60) in Chinese patients (pts) with newly diagnosed, advanced ovarian cancer (OC), regardless of biomarker status. As response to chemotherapy is deemed to be associated with prognosis in OC, this subgroup analysis of the PRIME study aims to better understand niraparib treatment effect in pts based on response to first-line platinum-based chemotherapy (1L CT). Methods: This randomized, double-blind, PBO-controlled, phase 3 trial enrolled adults with newly diagnosed, stage III or IV OC who achieved a complete response (CR) or partial response (PR) to 1L CT and received primary or interval cytoreductive surgery, irrespective of residual disease status after surgery. Pts were randomized (2:1) to receive niraparib or PBO, whose starting doses were individualized based on baseline bodyweight and platelet count, with stratification according to status of germline BRCA mutations (yes or no), tumor homologous recombination status (deficient or proficient), receipt of neoadjuvant chemotherapy (yes or no), and clinical response to 1L CT (CR or PR). This prespecified exploratory analysis reports progression-free survival (PFS) and HRs based on clinical response to 1L CT. The data cut-off date was 30 September 2021. Results: Of the 384 pts randomized, 315 (82.0%) and 69 (18.0%) had a CR (212 niraparib, 103 PBO) or PR (43 niraparib, 26 PBO) to 1L CT, respectively. Baseline characteristics are presented in the Table. The overall PFS median follow-up was 27.5 months. Niraparib significantly extended PFS compared with PBO: the median PFS was 29.4 months for niraparib versus 8.3 months for PBO (HR=0.45; 95% CI, 0.32–0.61; P<0.001) in the CR group and was 19.3 months for niraparib versus 8.3 months for PBO (HR=0.45; 95% CI, 0.23–0.86; P=0.014) in the PR group. Conclusions: In pts with newly diagnosed advanced OC, PFS was substantially prolonged with niraparib versus PBO, regardless of response to chemotherapy and biomarker status. Moreover, pts who achieved a CR appeared to receive larger PFS benefit from niraparib than those with a PR. Clinical trial information: NCT03709316. [Table: see text]
Real-world outcomes associated with bevacizumab combined with chemotherapy in platinum-resistant ovarian cancer.
Authors: Moffat Gordon Taylor , Kong Weidong , Booth Christopher M. , Ethier Josee-Lyne
Published: June 2022

5555

Background: In the pivotal Aurelia study, addition of bevacizumab (bev) to physician’s choice chemotherapy (paclitaxel, liposomal doxorubicin or topotecan) for platinum-resistant (PL-R) ovarian cancer (OC) was associated with improved progression-free survival (PFS; 6.7 vs 3.4 mos; hazard ratio (HR) 0.48, p = 0.001) but not overall survival (OS; 16.6 vs 13.3 mos HR 0.85, p = 0.174); the latter finding may relate to extensive crossover. In an exploratory subgroup analysis by treatment arm, benefits were particularly marked for bev + paclitaxel where median PFS (mPFS) increased from 3.9 to 10.4 mos (HR 0.46; 95%CI 0.30-0.71) and increases in OS approached statistical significance (HR 0.65; 95%CI, 0.42-1.02; 22.4 v 13.2 mos). Here we describe utilization of bev for PL-R OC and outcomes in routine clinical practice. Methods: The Ontario Cancer Registry and the New Drug Funding Program databases were utilized to identify all patients treated with bev plus chemotherapy (paclitaxel, liposomal doxorubicin or topotecan) for PL-R OC following its approval in 2017. Time on treatment (ToT) was defined as time from first to last bev treatment; this was used as a surrogate for PFS in routine practice. Median OS (mOS) was determined using the Kaplan-Meier method. Factors associated with ToT and OS were identified using a Cox proportional hazard model. A before and after comparison analysis was performed to determine mOS for patients treated pre- (2011-2017) and post-bev (2017-2019) approval. Results: From Oct 2017 to Dec 2019, 180 patients received bev + chemotherapy for first-line PL-R OC. Mean age was 63 years old, and 80% had serous OC. Bev was most often combined with liposomal doxorubicin (64 %) followed by paclitaxel (34%) and topotecan (2%). Median ToT was 3 months and OS was 11 months. ToT and OS were longer in patients who received paclitaxel as chemotherapy backbone (5 mos [ToT]; 14 mos [OS]) than those who received bev with liposomal doxorubicin (2 mos; 9 mos) or topotecan (2 mos; 6 mos). In multivariable models, ToT was superior in patients who received bev + paclitaxel than bev + liposomal doxorubicin (HR 0.40; 95%CI 0.28-0.57; p < 0.0001), and worse with longer time from diagnosis to bev start (1.03; 1.01-1.05; p = 0.0120). OS was also significantly longer in those who received paclitaxel vs liposomal doxorubicin (HR 0.54; 95%CI 0.30-0.98; p = 0.043). In a before and after analysis, patients treated in the pre- (n = 1290) and post-bev (n = 360) era had mOS of 8 and 9 months respectively. Post mOS increased for patients receiving paclitaxel (7 vs 12 months) but not with liposomal doxorubicin (9 vs 7 months). Conclusions: ToT and OS associated with bev for PL-R OC are shorter in a real-world population compared to results reported in AURELIA. ToT and OS were longer with bev + paclitaxel than with other chemotherapy agents.
Breast cancer incidence in patients with BRCA-related advanced ovarian cancer receiving olaparib-based maintenance therapy: A pooled analysis from phase III clinical trials.
Authors: Bartoletti Michele , Montico Marcella , Mazzeo Roberta , De Scordilli Marco , Musacchio Lucia , Lucia Emilio , Giorda Giorgio , Massarut Samuele , Urbani Martina , Miolo Gianmaria , Viel Alessandra , Garutti Mattia , Da Ros Lucia , Scalone Simona , Nicoloso Milena , Corsetti Serena , Sorio Roberto , Lorusso Domenica , Pignata Sandro , Puglisi Fabio
Published: June 2022

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Background: As the prognosis of BRCA-related advanced ovarian cancer (AOC) continues to improve thanks to the introduction of targeted therapies like poly ADP-ribose polymerase inhibitors (PARPi) and bevacizumab, the occurrence of second primary tumors, in particular breast cancer (BC), is assumed to be more common. Despite this, data on the incidence of BC in this population are poor and guidelines for BC screening or risk reducing strategies are lacking. Methods: Published data from recent PARPi-based, phase III clinical trials involving germline BRCA mutated AOC were reviewed and analyzed. Only studies in which the incidence of at least one second primary solid tumor was reported were included. Cases of second primary BC cancers were pooled to calculate cumulative incidence according to the median follow-up period for each trial. 95% confidence interval (CI) was considered. Results: Four trials (SOLO1, PAOLA1, SOLO2 and SOLO3) involving 1186 germline BRCA 1-2 mutated AOC patients were included ( BRCA1, n = 816; BRCA2, n = 360; BRCA1 + BRCA2, n = 4; missing, n = 6). In all trials, patients were randomized to receive olaparib +/- bevacizumab (n = 788) versus placebo or standard therapies (n = 398). Median age at diagnosis of AOC was 56 years (range, 29-87). With a follow-up ranging from 3.9 months to 5 years, 16 new cases of BC were recorded, 10 in PARPi-based arms and 6 in control arms. Only two patients had a previous history of BC. The total cumulative incidence of BC was 1.37% (95% CI, 0.77-2.18), while cumulative incidences were 1.26% (95% CI, 0.61-2.31) and 1.51% (95% CI, 0.55-3.25) in PARPi-based arms and control arms, respectively. In a sensitivity analysis excluding the SOLO3 trial with the shortest follow-up, the total cumulative incidence was 1.63% (95% CI, 0.92-2.67). Other 20 cases of second primary solid tumors were registered, including 4 cases of non-small cell lung cancer. Conclusions: Patients with germline BRCA-related AOC receiving PARPi-based maintenance therapy can be reassured about the risk of second primary BC and intensive screening should be avoided at least in early treatment phase. More data with long term follow-up are needed.
MOONSTONE/GOG-3032: Interim analysis of a phase 2 study of niraparib + dostarlimab in patients (pts) with platinum-resistant ovarian cancer (PROC).
Authors: Randall Leslie M. , O'Malley David M. , Monk Bradley J. , Coleman Robert L. , Gaillard Stephanie , Adams Sarah F. , Duska Linda R. , Cappuccini Fabio , Dalton Heather , Holloway Robert W. , Huang Marilyn , Chon Hye Sook , Cloven Noelle Gillette , ElNaggar Adam , O'Cearbhaill Roisin Eilish , Waggoner Steven E. , Wang Zebin , Zhi Eric , Samnotra Vivek , Konstantinopoulos Panagiotis A.
Published: June 2022

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Background: PROC is poorly responsive to anticancer therapy. PARP inhibitors such as niraparib may increase neoantigen load and synergize with anti-PD-1 agents. TOPACIO reported a preliminary objective response rate (ORR: 18%) and disease control rate (DCR: 65%) to niraparib + pembrolizumab in pts with OC of any BRCA status. MOONSTONE sought to determine efficacy in pts without BRCA mutation ( BRCAm). Methods: In this phase 2 open-label, single-arm study, eligible pts received 1–3 prior lines of therapy including platinum, taxane, and bevacizumab, had RECIST v1.1 radiographic progression within 6 mo of last platinum line and had no known germline BRCAm. Pts were treated with niraparib 300/200 mg PO daily (based on weight/platelets) and 500 mg dostarlimab IV Q3W (cycles 1–4) followed by 1000 mg Q6W until disease progression, toxicity or consent withdrawal. Programmed death-ligand 1 (PD-L1) positive status was determined by Ventana SP263 assay using visually-estimated combined positive score ≥5%. The primary endpoint was investigator-assessed ORR per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), DCR, and safety. Futility was prespecified as ≤5 responses in the first 40 pts. Results: At interim analysis (data cutoff Oct 6, 2021), 41 pts were enrolled; median age was 65.0 y (range 35–77). At baseline, 8 (20%)/22 (54%)/11 (27%) pts had received 1/2/3 prior lines of therapy, respectively; 26 (63%) pts had primary resistance to platinum therapy and 15 (37%) were sensitive to first platinum treatment. Overall, tumors were PD-L1+/PD-L1–/unknown in 13 (32%)/25 (61%)/3 (7%), respectively. Efficacy results are shown in the Table. Treatment-related adverse events were reported in 95% of pts, most commonly nausea (56%), fatigue (34%), vomiting (32%), and anemia (29%). Conclusions: PROC remains difficult to treat; the ORR observed with niraparib + dostarlimab did not reach the threshold for 2nd-stage accrual in this cohort of pts with PROC, no known BRCAm, and prior bevacizumab treatment. PD-L1 status did not predict response; HRD testing is in process. Although DCR was 29%, futility was declared based on low ORR. The safety of the combination was similar to the safety profile of each monotherapy. Clinical trial information: NCT03955471. [Table: see text]
Integrated safety summary of single-agent mirvetuximab soravtansine in patients with folate receptor α (FRα)-positive recurrent ovarian cancer: Phase 1 and 3 clinical trials.
Authors: Moore Kathleen N. , Lorusso Domenica , Oaknin Ana , Oza Amit M. , Colombo Nicoletta , Van Gorp Toon , O'Malley David M. , Banerjee Susana N. , Murphy Conleth G. , Harter Philipp , Konecny Gottfried E. , Pautier Patricia , Method Michael W. , Wang Jiuzhou , Birrer Michael J. , Coleman Robert L. , Matulonis Ursula A.
Published: June 2022

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Background: Available chemotherapies for platinum-resistant ovarian cancer (PROC) have limited clinical activity and considerable toxicity. Mirvetuximab soravtansine (MIRV) is a first-in-class antibody drug conjugate (ADC) comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin-targeting agent that has demonstrated significant anti-tumor activity in this difficult to treat population. The objective is to characterize the tolerability profile of MIRV in a pooled analysis of experience when administered as monotherapy in patients (pts) with FRα positive recurrent ovarian cancer. Methods: Retrospective pooled analysis included pts enrolled across three studies: phase 1 first-in-human, phase 3 FORWARD I, and phase 3 SORAYA. Analysis included pts with FRα positive recurrent ovarian cancer and those pts with low, medium, and high FRα expression by immunohistochemistry (Roche FOLR1 Assay ≥ 25% of cells with PS2+ staining intensity). All pts received intravenous MIRV at 6 mg/kg, adjusted ideal body weight, on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity. Results: 464 pts were included from 15 countries, with key characteristics: median age 63 yrs, 87% 1-3 prior therapies, 91% platinum free interval ≤6 months, 65% prior bevacizumab, and 25% prior PARPi. The most common treatment-related adverse events (TRAE) (all grade, grade 3+) included blurred vision (42%, 3%), nausea (40%, 2%), diarrhea (33%, 2%), fatigue (31%, 2%), keratopathy (26%, 3%), and dry eye (22%, 1%). TRAEs leading to a dose delay or reduction occurred in 33% and 21% of pts, respectively. Seven % discontinued due to a TRAE. Four pts ( < 1%) discontinued MIRV due to an ocular event. Ninety % of pts with a grade 2+ blurred vision resolved to grade 0 or 1, 93% of pts with grade 2+ keratopathy resolved to grade 0 or 1. No corneal ulcers or perforation have been reported and no patient with a serious ocular event has been reported to have permanent sequelae. Conclusions: In a pooled analysis of 464 patients, MIRV monotherapy has a differentiated and predictable safety profile consisting primarily of low grade and reversible gastrointestinal and ocular events. These events were managed with supportive care and dose modifications if needed, with a low rate of treatment-related discontinuation. The safety profile of MIRV in recurrent ovarian cancer along with the anti-tumor activity in PROC (32.4% ORR Matulonis SGO 2022) support a favorable benefit/risk in this population. Clinical trial information: NCT01609556, NCT04296890, NCT02631876.