Publications by authors named "Amit Oza"

230 Publications

Prospective observational study and serosurvey of SARS-CoV-2 infection in asymptomatic healthcare workers at a Canadian tertiary care center.

PLoS One 2021 16;16(2):e0247258. Epub 2021 Feb 16.

University Health Network, Toronto, Ontario, Canada.

Health care workers (HCWs) are at higher risk for SARS-CoV-2 infection and may play a role in transmitting the infection to vulnerable patients and members of the community. This is particularly worrisome in the context of asymptomatic infection. We performed a cross-sectional study looking at asymptomatic SARS-CoV-2 infection in HCWs. We screened asymptomatic HCWs for SARS-CoV-2 via PCR. Complementary viral genome sequencing was performed on positive swab specimens. A seroprevalence analysis was also performed using multiple assays. Asymptomatic health care worker cohorts had a combined swab positivity rate of 29/5776 (0.50%, 95%CI 0.32-0.75) relative to a comparative cohort of symptomatic HCWs, where 54/1597 (3.4%) tested positive for SARS-CoV-2 (ratio of symptomatic to asymptomatic 6.8:1). SARS-CoV-2 seroprevalence among 996 asymptomatic HCWs with no prior known exposure to SARS-CoV-2 was 1.4-3.4%, depending on assay. A novel in-house Coronavirus protein microarray showed differing SARS-CoV-2 protein reactivities and helped define likely true positives vs. suspected false positives. Our study demonstrates the utility of routine screening of asymptomatic HCWs, which may help to identify a significant proportion of infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886177PMC
February 2021

Angiogenesis Inhibitors as Anti-Cancer Therapy Following Renal Transplantation: A Case Report and Review of the Literature.

Curr Oncol 2021 Jan 22;28(1):661-670. Epub 2021 Jan 22.

Division of Medical Oncology & Hematology, Bras Family Drug Development Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G2M9, Canada.

Solid organ transplant recipients on long-term immunosuppressive medication are at increased risk of developing malignancy, and treatment of advanced cancers with angiogenesis inhibitors in this context has not been widely studied. We present a case of recurrent high-grade serous ovarian carcinoma treated with paclitaxel and bevacizumab in the context of prior renal transplantation where the patient responded well to treatment with controlled toxicities, discussing the potential for increased rates of adverse events and drug interactions in this select population.
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http://dx.doi.org/10.3390/curroncol28010064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924357PMC
January 2021

Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial.

Lancet 2021 01;397(10271):281-292

Princess Margaret Cancer Centre, Toronto, ON, Canada. Electronic address:

Background: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer.

Methods: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual.

Findings: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group).

Interpretation: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required.

Funding: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(20)32554-XDOI Listing
January 2021

Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study.

Gynecol Oncol 2021 Jan 18. Epub 2021 Jan 18.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network/Sinai Health Systems, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada; Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: Findings on impact of mismatch repair deficiency (MMRd) on patient outcomes in endometrial cancer (EC) have been inconsistent to date. The objective of this study was to compare the oncologic outcomes and recurrence patterns between MMRd and MMR-intact (MMRi) endometrioid EC (EEC).

Methods: Between 2015 and 2018, we prospectively recruited 492 EEC cases from three cancer centers in Ontario, Canada. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinicopathological, survival and recurrence patterns were compared between MMRd and MMRi cases.

Results: Of 492 EEC, 348 were MMRi (71%) and 144 were MMRd (29%) with median follow-up of 16.8 months (0-69.6). MMRd tumors tended to be grade 2 or 3 (56% vs. 29%, p < 0.001), with propensity for lymphovascular space invasion (28% vs. 18%, p = 0.024), lymph node involvement (7% vs. 5%, p < 0.001) and received more adjuvant treatment (46% vs. 33%, p = 0.027). This group also had significantly lower 3-year recurrence-free survival (78% vs. 90%, p = 0.014) although there was no difference in OS (p = 0.603). MMRd cases were more likely to recur in retroperitoneal lymph nodes (p = 0.045). Upon subgroup analysis, MLH1 methylated tumors had the worst prognostic features and survival outcomes.

Conclusions: MLH1 methylated EECs exhibit more aggressive features compared to other MMRd and MMRi EECs. This may indicate an inherent difference in tumor biology, suggesting the importance of individualized management based on EC molecular phenotype.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.002DOI Listing
January 2021

Optimizing clinical research procedures in public health emergencies.

Med Res Rev 2021 03 11;41(2):725-738. Epub 2020 Nov 11.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

Public Health Emergencies of International Concern, such as the coronavirus disease 2019 pandemic, have a devastating impact on an individual and societal level, and there is an urgent need to learn, understand and bridge the therapeutic gap at a time of extreme stress on the patient, health care systems and staff. Well-designed, controlled clinical trials play a crucial role in the discovery of novel diagnostic and management strategies; however, these catastrophic circumstances pose unique challenges in initiating research studies at institutional, national, and international levels, highlighting the importance of a coordinated, collaborative approach. This review discusses key elements necessary to consider for developing clinical trials within a Public Health Emergency setting.
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http://dx.doi.org/10.1002/med.21749DOI Listing
March 2021

Measuring Quality of Life in Ovarian Cancer Clinical Trials-Can We Improve Objectivity and Cross Trial Comparisons?

Cancers (Basel) 2020 Nov 7;12(11). Epub 2020 Nov 7.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1X6, Canada.

Epithelial ovarian cancer (EOC) remains a lethal disease for the majority of women diagnosed with it worldwide. For the majority of patients, diagnosis occurs late, in the advanced setting. Disease-induced as well as treatment-related adverse events can negatively impact quality of life (QoL). Research to date has captured these data through use of patient-related outcomes (PROs) and, increasingly, has become an area of increased attention and focus in clinical trial reporting. QoL/PRO measurements in EOC clinical trials at different transition points in a patient's journey are increasingly being recognized by patients, clinicians and regulatory agencies as the key determinants of treatment benefit. Various context-specific PROs and PRO endpoints have been described for clinical trials in EOC. Standardized approaches and checklists for incorporating PRO endpoints in clinical trials have been proposed. In a real-world clinical practice setting, PRO/QoL measures, which are meaningful, valid, reliable, feasible and acceptable to patients and clinicians, need to be implemented and used. These may assist by serving as screening tools; helping with the identification of patient preferences to aid in decision making; improving patient-provider communication; facilitating shared decision making. Importantly, they may also improve quality of care through an increasingly patient-centered approach. Potential areas of future research include assessment of anxiety, depression and other mental health issues. In good prognostic groups, such as maintenance clinical trials, following patients beyond progression will capture possible downstream effects related to delaying the psychological trauma of relapse, symptoms due to disease progression and side-effects of subsequent chemotherapy. Identifying PRO endpoints in next-generation-targeted therapies (including immunotherapies) also warrants investigation.
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http://dx.doi.org/10.3390/cancers12113296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694966PMC
November 2020

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers.

Int J Gynecol Cancer 2020 Dec 20;30(12):1951-1958. Epub 2020 Oct 20.

Gynecologic Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada

Objectives: For synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.

Methods: 30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.

Results: Of 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.

Conclusions: There was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.
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http://dx.doi.org/10.1136/ijgc-2020-001927DOI Listing
December 2020

Across barriers: poly ADP-ribose polymerase inhibitors beyond progression in high grade serous ovarian cancer with brain metastases.

Int J Gynecol Cancer 2021 Jan 30;31(1):139-143. Epub 2020 Sep 30.

Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada

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http://dx.doi.org/10.1136/ijgc-2020-001849DOI Listing
January 2021

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy.

Eur J Cancer 2020 11 23;139:59-67. Epub 2020 Sep 23.

Université Paris Descartes, Paris, France; ARCAGY-GINECO, France.

Background: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo.

Methods: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV).

Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST.

Conclusions: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.
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http://dx.doi.org/10.1016/j.ejca.2020.08.021DOI Listing
November 2020

Biomarkers of outcome to weekly paclitaxel in epithelial ovarian cancer.

Gynecol Oncol 2020 Nov 8;159(2):539-545. Epub 2020 Sep 8.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada. Electronic address:

Objective: We sought to evaluate the role of intrinsic chromosomal aberrations in determining favorable outcome to weekly paclitaxel (WP) in patients with epithelial ovarian cancer (EOC).

Methods: We evaluated the common genomic aberrations of two patients with EOC and exceptional WP response in the GENIUS study (NCT03740503). We then searched for potential markers of unusual outcomes to WP in a validation cohort. We performed shallow whole genome sequencing (sWGS) in the tumor tissue of women with EOC considered as short-responders (SR; progression with ≤3 cycles) and long-responders (LR; response at ≥8 cycles) to WP monotherapy.

Results: We identified two women with exceptional response to WP, lasting over four years, who shared chromosome 8 gain as a common genomic aberration. In order to validate our findings, we reviewed 188 patients with EOC treated with WP and selected 61 women (39 SR, 22 LR) with unusual responses. By sWGS, there was no differential alterations in the copy number changes in chromosome 8, or in genes related to angiogenesis, tubulin superfamily, cell-cycle, apoptosis and paclitaxel metabolism or transportation pathways. Amongst the LR group, we identified six exceptionally long responders (ExLR), with responses lasting over a year. In an exploratory analysis, there was increased amplification of angiogenesis (VEGFB, MMP9), tubulin superfamily (TSC2) and apoptosis related genes (BCL2L1, BAD) in ExLR compared to SR. We identified one patient with a complete response to WP for over 7 years. Molecular profiling identified unique amplifications in interleukin related genes (CXCR1, CXCR2, IL1A, IL1B), not detected in other patients.

Conclusion: Intrinsic tumor pathways may impact outcome with weekly paclitaxel monotherapy and further investigations are required.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.032DOI Listing
November 2020

DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment.

Int J Gynecol Cancer 2020 Nov 2;30(11):1824-1828. Epub 2020 Sep 2.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

Background: With the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously received a PARP inhibitor in the maintenance setting and for whom no second maintenance standard of care exists. DUETTE (NCT04239014) will evaluate the combination of ceralasertib (a potent, selective inhibitor of the serine/threonine kinase ataxia telangiectasia and Rad3-related protein (ATR) + olaparib, or olaparib monotherapy, compared with placebo, in this patient population of unmet need.

Primary Objective: The primary objective is to assess the efficacy of ceralasertib + olaparib combination, and olaparib monotherapy, compared with placebo, as second maintenance therapy in platinum-sensitive relapsed ovarian cancer.

Study Hypothesis: This study will test the hypothesis that ceralasertib + olaparib, or olaparib monotherapy, is tolerable, and effective at prolonging progression-free survival compared with placebo.

Trial Design: This is a phase II, multicenter study where patients will be randomized in a 1:1:1 ratio to receive either (Arm 1) ceralasertib + olaparib, (Arm 2) olaparib monotherapy, or (Arm 3) placebo. The olaparib and placebo arms will be double-blinded, whereas the ceralasertib + olaparib arm will be open label. Patients will be stratified according to status, and response to platinum-based chemotherapy.

Major Inclusion/exclusion Criteria: Eligible patients will have histologically diagnosed high-grade epithelial ovarian cancer, with platinum-sensitive relapse on, or after, completion of at least 6 months of any prior PARP inhibitor maintenance therapy (a minimum of 12 months is required if the patient received PARP inhibitor maintenance following first-line chemotherapy). If the prior PARP inhibitor used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Disease relapse in the second-line or third-line setting is allowed. Patients who have received secondary debulking surgery are potentially eligible if they meet all other inclusion criteria.

Primary Endpoints: The primary endpoint is progression-free survival determined by blinded independent central review according to RECIST 1.1, with sensitivity analysis of progression-free survival using investigator assessments according to RECIST 1.1.

Sample Size: 192 patients.

Estimated Dates For Completing Accrual And Presenting Results: December 2022.

Trial Registration: NCT04239014.
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http://dx.doi.org/10.1136/ijgc-2020-001694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656147PMC
November 2020

The effect of age on efficacy, safety and patient-centered outcomes with rucaparib: A post hoc exploratory analysis of ARIEL3, a phase 3, randomized, maintenance study in patients with recurrent ovarian carcinoma.

Gynecol Oncol 2020 Oct 26;159(1):101-111. Epub 2020 Aug 26.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

Background: In the phase 3 trial ARIEL3, maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib provided clinical benefit versus placebo for patients with recurrent, platinum-sensitive ovarian cancer. Here, we evaluate the impact of age on the clinical utility of rucaparib in ARIEL3.

Methods: Patients with platinum-sensitive, recurrent ovarian carcinoma with ≥2 prior platinum-based chemotherapies who responded to their last platinum-based therapy were enrolled in ARIEL3 and randomized 2:1 to rucaparib 600 mg twice daily or placebo. Exploratory, post hoc analyses of progression-free survival (PFS), patient-centered outcomes (quality-adjusted PFS [QA-PFS] and quality-adjusted time without symptoms or toxicity [Q-TWiST]), and safety were conducted in three age subgroups (<65 years, 65-74 years, and ≥75 years).

Results: Investigator-assessed PFS was significantly longer with rucaparib than placebo in patients aged <65 years (rucaparib n = 237 vs placebo n = 117; median, 11.1 vs 5.4 months; hazard ratio [HR]: 0.33 [95% confidence interval (95% CI) 0.25-0.43]; P < 0.0001) and 65-74 years (n = 113 vs n = 64; median, 8.3 vs 5.3 months; HR 0.43 [95% CI 0.29-0.63]; P < 0.0001) and numerically longer in patients aged ≥75 years (n = 25 vs n = 8; median, 9.2 vs 5.5 months; HR 0.47 [95% CI 0.16-1.35]; P = 0.1593). QA-PFS and Q-TWiST were significantly longer with rucaparib than placebo across all age subgroups. Safety of rucaparib was generally similar across the age subgroups.

Conclusions: Efficacy, patient-centered outcomes, and safety of rucaparib were similar between age subgroups, indicating that all eligible women with recurrent ovarian cancer should be offered this therapeutic option, irrespective of age. https://clinicaltrials.gov/ct2/show/NCT01968213.
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http://dx.doi.org/10.1016/j.ygyno.2020.05.045DOI Listing
October 2020

Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma.

J Clin Oncol 2020 10 24;38(30):3494-3505. Epub 2020 Aug 24.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo.

Patients And Methods: Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data.

Results: The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); -mutant cohort (130 rucaparib 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, -mutant cohort, HRD cohort, and wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib.

Conclusion: The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.
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http://dx.doi.org/10.1200/JCO.19.03107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571791PMC
October 2020

MILO/ENGOT-ov11: Binimetinib Versus Physician's Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum.

J Clin Oncol 2020 11 21;38(32):3753-3762. Epub 2020 Aug 21.

Belgium and Luxemburg Gynaecological Oncology Group, University Hospitals Leuven, Leuven, Belgium.

Purpose: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC.

Methods: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety.

Results: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent.

Conclusion: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and mutation might predict response to binimetinib.
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http://dx.doi.org/10.1200/JCO.20.01164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655017PMC
November 2020

Moving Beyond BRCA-Incorporating Molecular Assays into Ovarian Cancer Trials.

Clin Cancer Res 2020 Oct 14;26(20):5271-5273. Epub 2020 Aug 14.

Princess Margaret Cancer Centre, University Health Network. Toronto, Ontario, Canada.

PrOTYPE is a locked down assay validated to Institute of Medicine standards, using NanoString technology to classify high-grade serous ovarian cancer into four defined subgroups. Future directions will include prospective-retrospective analysis and prospective clinical validation to define the predictive role of this assay and its role in influencing treatment decisions..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2429DOI Listing
October 2020

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer.

Cancer 2020 Nov 18;126(22):4886-4894. Epub 2020 Aug 18.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Sinai Health Systems, Toronto, Ontario, Canada.

Background: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.

Methods: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.

Results: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.

Conclusions: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.
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http://dx.doi.org/10.1002/cncr.33144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693219PMC
November 2020

An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors.

J Immunother Cancer 2020 08;8(2)

Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Purpose: To evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically 'cold' solid tumors to immune checkpoint inhibitor durvalumab.

Experimental Design: PD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1-14 (cycles 1-3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1-21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes.

Results: A total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected 'viral mimicry' inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10).

Conclusions: The evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents.

Trial Registration Number: NCT02811497.
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http://dx.doi.org/10.1136/jitc-2020-000883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406114PMC
August 2020

Efficacy of Maintenance Olaparib for Patients With Newly Diagnosed Advanced Ovarian Cancer With a BRCA Mutation: Subgroup Analysis Findings From the SOLO1 Trial.

J Clin Oncol 2020 10 4;38(30):3528-3537. Epub 2020 Aug 4.

Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK.

Purpose: In SOLO1, maintenance olaparib (300 mg twice daily) significantly improved progression-free survival (PFS) for patients with newly diagnosed - and/or -mutated advanced ovarian cancer compared with placebo (hazard ratio [HR], 0.30; 95% CI, 0.23 to 0.41; median not reached 13.8 months). We investigated PFS in SOLO1 for subgroups of patients based on preselected baseline factors.

Patients And Methods: Investigator-assessed PFS subgroup analyses of SOLO1 included clinical response after platinum-based chemotherapy (complete [CR] or partial response [PR]), surgery type (upfront or interval surgery), disease status after surgery (residual or no gross residual disease), and BRCA mutation status ( or ). Additionally, we evaluated PFS in patients with stage III disease who underwent upfront surgery and had no gross residual disease. We also report objective response rate.

Results: The risk of disease progression or death was reduced with olaparib compared with placebo by 69% (HR, 0.31; 95% CI, 0.21 to 0.46) and 63% (HR, 0.37; 95% CI, 0.24 to 0.58) in patients undergoing upfront or interval surgery; 56% (HR, 0.44; 95% CI, 0.25 to 0.77) and 67% (HR, 0.33; 95% CI, 0.23 to 0.46) in patients with residual or no residual disease after surgery; 66% (HR, 0.34; 95% CI, 0.24 to 0.47) and 69% in women with clinical CR or PR at baseline (HR, 0.31; 95% CI, 0.18 to 0.52); and 59% (HR, 0.41; 95% CI, 0.30 to 0.56) and 80% (HR 0.20; 95% CI, 0.10 to 0.37) in patients with a or mutation, respectively.

Conclusion: Patients with newly diagnosed advanced ovarian cancer achieve substantial benefit from maintenance olaparib treatment regardless of baseline surgery outcome, response to chemotherapy, or BRCA mutation type.
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http://dx.doi.org/10.1200/JCO.20.00799DOI Listing
October 2020

Adjuvant treatment in early stage cervical cancer-does more equal better?

Int J Gynecol Cancer 2020 Sep 20;30(9):1467-1468. Epub 2020 Jul 20.

Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1136/ijgc-2020-001840DOI Listing
September 2020

Efficacy and safety updates of poly ADP-ribose polymerase (PARP) inhibitor maintenance in ovarian cancer from ASCO 2020.

Int J Gynecol Cancer 2020 08 9;30(8):1256-1257. Epub 2020 Jul 9.

Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

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http://dx.doi.org/10.1136/ijgc-2020-001723DOI Listing
August 2020

COVID-19 Testing in Patients with Cancer: Does One Size Fit All?

Clin Cancer Res 2020 09 2;26(18):4737-4742. Epub 2020 Jul 2.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

The COVID-19 global pandemic has drastically impacted cancer care, posing challenges in treatment and diagnosis. There is increasing evidence that cancer patients, particularly those who have advanced age, significant comorbidities, metastatic disease, and/or are receiving active immunosuppressive therapy may be at higher risk of COVID-19 severe complications. Controlling viral spread from asymptomatic carriers in cancer centers is paramount, and appropriate screening methods need to be established. Universal testing of asymptomatic cancer patients may be key to ensure safe continuation of treatment and appropriate hospitalized patients cohorting during the pandemic. Here we perform a comprehensive review of the available evidence regarding SARS-CoV-2 testing in asymptomatic cancer patients, and describe the approach adopted at Princess Margaret Cancer Centre (Toronto, Canada) as a core component of COVID-19 control.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2224DOI Listing
September 2020

A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive -mutant Ovarian Cancer.

Clin Cancer Res 2020 Sep 1;26(18):4767-4776. Epub 2020 Jul 1.

Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes -mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in -mutated ovarian cancer.

Patients And Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with -mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.

Results: A total of 121 patients were randomized to adavosertib (A+C; = 59) and placebo (P+C; = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9-9.9) vs. 7.3 months (5.6-8.2); HR 0.63 (95% CI, 0.38-1.06); two-sided = 0.080], meeting the predefined significance threshold ( < 0.2). Clinical benefit was observed following A+C for patients with different mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).

Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0219DOI Listing
September 2020

Measurement Tool of Chemotherapy Sensitivity in Advanced Ovarian Cancer.

Clin Cancer Res 2020 Sep 29;26(17):4432-4434. Epub 2020 Jun 29.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

The modeled Ca125 ELIMination rate constant K (KELIM) can be used as a measure of chemotherapy sensitivity in women with newly diagnosed advanced epithelial ovarian cancer who are being treated with neoadjuvant chemotherapy. This marker may aid in decision-making regarding surgical resection and alternate systemic treatments in this cohort..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1376DOI Listing
September 2020

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer.

Cancers (Basel) 2020 Jun 17;12(6). Epub 2020 Jun 17.

Division of Medical Oncology & Hematology, Bras Family Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.

Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through reversion mutations and epigenetic upregulation of Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.
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http://dx.doi.org/10.3390/cancers12061607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352566PMC
June 2020

The role of maintenance therapy in ovarian cancer.

Authors:
Amit M Oza

Clin Adv Hematol Oncol 2020 Feb;18(2):98-101

University of Toronto, Toronto, Ontario, Canada.

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February 2020

The World Ovarian Cancer Coalition Every Woman Study: identifying challenges and opportunities to improve survival and quality of life.

Int J Gynecol Cancer 2021 Feb 14;31(2):238-244. Epub 2020 Jun 14.

Target Ovarian Cancer, London, UK.

Introduction: With the global incidence of ovarian cancer set to rise by 55% to 371 000 per year by 2035, current 5-year survival rates below 50%, and 15% of women with ovarian cancer dying within 2 months of diagnosis, urgent action is required to improve survival and quality of life.

Objective: To deal with the evidence gap relating to the experience of women with the disease around the globe and identify opportunities to drive progress.

Methods: The study included a review of global trends in incidence, mortality, and survival (October 2017); qualitative interviews with women and clinicians in 16 countries (December 2017); and an online survey for women available in 15 different languages (open for 2 months, March to early May 2018). Women were eligible to participate if they had been diagnosed in the previous 5 years and were proficient in one of the 15 languages offered.

Results: A total of 1531 women from 44 countries took part in the analysis. On average, 69.1% of women were not aware of ovarian cancer before their own diagnosis, varying from 50.9% (Hungary) to 86.4% (Brazil). A total of 78.3% of symptomatic women sought medical help, varying from 62.8% (Japan) to 87.7% (UK). Fewer than half of the women visited a doctor within 1 month (46.3%) of experiencing symptoms, varying from 38.5% (USA) to 77.3% (Germany), and a quarter of women waited 3 months or more. On average, 43.2% of women were diagnosed within 1 month of visiting a doctor, ranging from 30% (UK) to 62.3% (Italy). The average estimated time from experiencing symptoms to diagnosis was 31 weeks, but this ranged from 21.3 (Germany) to 39.7 (Brazil). Rates of post-diagnosis genetic testing ranged from 5.0% (Japan) to 79.1% (USA). Clinicians indicated that access to specialist treatment in high-volume centers varies greatly by country and region.

Conclusion: The findings of this study identify some of the major challenges and opportunities to improve the time to diagnosis and management of women with ovarian cancer. These problems vary widely by country, and reducing the variability is an important first step towards improving outcomes for women with ovarian cancer.
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http://dx.doi.org/10.1136/ijgc-2019-000983DOI Listing
February 2021

Low junctional adhesion molecule-A expression is associated with an epithelial to mesenchymal transition and poorer outcomes in high-grade serous carcinoma of uterine adnexa.

Mod Pathol 2020 11 8;33(11):2361-2377. Epub 2020 Jun 8.

Institut du Cancer de Montréal, Montreal, QC, H2X 0A9, Canada.

High-grade serous carcinoma of uterine adnexa (HGSC) is the most frequent histotype of epithelial ovarian cancer and has a poor 5-year survival rate due to late-stage diagnosis and the poor efficacy of standard treatments. Novel biomarkers of cancer outcome are needed to identify new targetable pathways and improve personalized treatments. Cell-surface screening of 26 HGSC cell lines by high-throughput flow cytometry identified junctional adhesion molecule 1 (JAM-A, also known as F11R) as a potential biomarker. Using a multi-labeled immunofluorescent staining coupled with digital image analysis, protein levels of JAM-A were quantified in tissue microarrays from three HGSC patient cohorts: a discovery cohort (n = 101), the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158), and the Canadian Cancer Trials Group OV16 cohort (n = 267). Low JAM-A level was associated with poorer outcome in the three cohorts by Kaplan-Meier (p = 0.023, p < 0.001, and p = 0.036, respectively) and was an independent marker of shorter survival in the COEUR cohort (HR = 0.517 (0.381-703), p < 0.001). When analyses were restricted to patients treated by taxane-platinum-based chemotherapy, low JAM-A protein expression was associated with poorer responses in the COEUR (p < 0.001) and OV16 cohorts (p = 0.006) by Kaplan-Meier. Decreased JAM-A gene expression was an indicator of poor outcome in gene expression datasets including The Cancer Genome Atlas (n = 606, p = 0.002) and Kaplan-Meier plotter (n = 1816, p = 0.024). Finally, we observed that tumors with decreased JAM-A expression exhibited an enhanced epithelial to mesenchymal transition (EMT) signature. Our results demonstrate that JAM-A expression is a robust prognostic biomarker of HGSC and may be used to discriminate tumors responsive to therapies targeting EMT.
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http://dx.doi.org/10.1038/s41379-020-0586-0DOI Listing
November 2020

EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression.

Clin Cancer Res 2020 Aug 22;26(16):4206-4215. Epub 2020 May 22.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Purpose: PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.

Patients And Methods: The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib-olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.

Results: Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in , or (19%); amplification (16%); upregulation (15%); and downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or upregulation had poor outcomes.

Conclusions: This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib-olaparib varied according to the PARPi resistance mechanism.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4121DOI Listing
August 2020

Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2020 05;21(5):710-722

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data.

Methods: In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213.

Findings: Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths.

Interpretation: In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports.

Funding: Clovis Oncology.
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http://dx.doi.org/10.1016/S1470-2045(20)30061-9DOI Listing
May 2020

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events.

Int J Gynecol Cancer 2020 07 9;30(7):903-915. Epub 2020 Apr 9.

Medical Oncology & Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment landscape in front-line and recurrent high-grade serous ovarian cancer. Maintenance strategies with PARPi have been assessed in randomized phase III trials in ovarian cancer; switch maintenance in the case of olaparib, niraparib, and rucaparib; and concurrent followed by continuation maintenance with veliparib. These studies have shown progression-free survival advantage with PARPi maintenance, with no major adverse changes in the quality of life; however, overall survival data remain immature to date. PARPi have also been incorporated in clinical practice as a single-agent treatment strategy in high-grade serous ovarian cancer, mainly in women who harbor alterations in the genes or have alterations in the homologous recombination deficiency (HRD) pathway. Contemporary studies are looking into potentially synergistic combination strategies with anti-angiogenics and immune checkpoint inhibitors, among others. The expansion of PARPi treatment has not been limited to ovarian cancer; talazoparib is licensed in patients with HER2-negative breast cancer with germline mutations (m), and front-line olaparib maintenance in patients with pancreatic cancer with germline m. Numerous studies assessing PARPi either in monotherapy or in combination with other agents are ongoing in multiple tumors, including prostate, endometrial, brain, and gastric cancers. Many patients are being treated with PARPi, some for prolonged periods of time. As a result, a thorough knowledge of the potential short- and long-term adverse events and their management is warranted to improve patient safety, treatment efficacy, and towards maintaining an appropriate dose intensity.
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http://dx.doi.org/10.1136/ijgc-2020-001288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398227PMC
July 2020