The open-label, single-arm, multicenter ORZORA trial (NCT02476968) evaluated the efficacy and safety of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) who ...had tumor BRCA mutations (BRCAm) of germline (g) or somatic (s) origin or non-BRCA homologous recombination repair mutations (HRRm) and were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment.
Patients received maintenance olaparib capsules (400 mg twice daily) until disease progression. Prospective central testing at screening determined tumor BRCAm status and subsequent testing determined gBRCAm or sBRCAm status. Patients with predefined non-BRCA HRRm were assigned to an exploratory cohort. The co-primary endpoints were investigator-assessed progression-free survival (PFS; modified Response Evaluation Criteria in Solid Tumors v1.1) in BRCAm and sBRCAm cohorts. Secondary endpoints included health-related quality of life (HRQoL) and tolerability.
177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3 months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3–22.1), 16.6 (12.4–22.2), 19.3 (14.3–27.6) and 16.4 (10.9–19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%) or no change (68.7%) in HRQoL and the safety profile was as expected.
Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm. Activity was also observed in patients with a non-BRCA HRRm. ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC.
•Clinical activity of maintenance olaparib in platinum-sensitive relapsed ovarian cancer was seen with any BRCA mutation.•This included activity in patients with somatic BRCA mutations.•Activity was also seen in patients with non-BRCA homologous recombination repair mutations.•Safety and tolerability were consistent with previous studies in this setting.
Patients with solid tumors have been a risk group since the beginning of the SARS‐CoV‐2 pandemic due to more significant complications, hospitalizations or deaths. The immunosuppressive state of ...cancer treatments or the tumor itself could influence the development of post‐vaccination antibodies. This study prospectively analyzed 89 patients under chemotherapy and/or immunotherapy, who received two doses of the mRNA‐1237 vaccine, and were compared with a group of 26 non‐cancer individuals. Information on adverse events and neutralizing antibodies against the ancestral strain of SARS‐CoV‐2 (WH1) have been analyzed. Local reactions accounted for 65%, while systemic reactions accounted for 46% of oncologic individuals/cancer patients. Regarding the response to vaccination, 6.7% of cancer patients developed low neutralizing antibody levels. Lower levels of neutralizing antibodies between cancer and non‐cancer groups were significant in individuals without previous SARS‐CoV‐2 infection, but not in previously infected individuals. We also observed that patients receiving chemotherapy or chemoimmunotherapy have significantly lower levels of neutralizing antibodies than non‐cancer individuals. In conclusion, our study confirms the importance of prioritizing cancer patients receiving anticancer treatment in SARS‐CoV‐2 vaccination programs.
Cancer patients are a risk group for SARS‐CoV‐2 infection. We determined the levels of anti‐SARS‐CoV‐2 plasma neutralizing antibodies post mRNA‐1273 vaccination and observed that cancer patients exhibit lower titers compared to non‐cancer individuals, particularly in individuals not previously infected by SARS‐CoV‐2. Additionally, we found an association between low levels of neutralizing antibodies and chemotherapy‐containing treatments, highlighting their prioritization in SARS‐CoV‐2 vaccination programs.
Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the ...immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (
= 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval CI: 40.9-95.2,
= 0.019; and NR vs. 56.1 months, 95% CI: 40.9-95.2,
= 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease,
status and stage (HR 2.48, 95% CI: 1.03-5.99,
= 0.043, and HR 2.91, 95% CI: 1.11-7.64,
= 0.03, respectively). In the IDS group (
= 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).
SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase which has been proposed as a putative prognostic factor in haematological cancers and certain solid tumours, although with ...controversial data. Here, we evaluate SAMHD1 function in ovarian cancer, both
and in ovarian cancer patients.
SAMHD1 expression was downregulated in ovarian cancer cell lines OVCAR3 and SKOV3 by RNA interference. Gene and protein expression changes in immune signalling pathways were assessed. SAMHD1 expression in ovarian cancer patients was evaluated by immunohistochemistry and survival analysis was performed according to SAMHD1 expression.
SAMHD1 knockdown induced a significant upregulation of proinflammatory cytokines concomitant to increased expression of the main RNA-sensors, MDA5 and RIG-I, and interferon-stimulated genes, supporting the idea that the absence of SAMHD1 promotes innate immune activation
. To assess the contribution of SAMHD1 in ovarian cancer patients, tumours were stratified in SAMHD1-low and SAMHD1-high expressing tumours, resulting in significantly shorter progression free survival (PFS) and overall survival (OS) in SAMHD1-high expression subgroup (
=0.01 and 0.04, respectively).
SAMHD1 depletion correlates with increased innate immune cell signalling in ovarian cancer cells. In clinical samples, SAMHD1-low expressing tumors showed increased progression free survival and overall survival irrespective of BRCA mutation status. These results point towards SAMHD1 modulation as a new therapeutic strategy, able to enhance innate immune activation directly in tumour cells, leading to improved prognosis in ovarian cancer.
Lung cancer patients represent a subgroup of special vulnerability in whom the SARS-CoV-2 infection could attain higher rates of morbidity and mortality. Therefore, those patients were recommended to ...receive SARS-CoV-2 vaccines once they were approved. However, little was known at that time regarding the degree of immunity developed after vaccination or vaccine-related adverse events, and more uncertainty involved the real need for a third dose. We sought to evaluate the immune response developed after vaccination, as well as the safety and efficacy of SARS-CoV-2 vaccines in a cohort of patients with lung cancer. Patients were identified through the Oncology/Hematology Outpatient Vaccination Program. Anti-Spike IgG was measured before any vaccine and at 3-6-, 6-9- and 12-15-month time points after the 2nd dose. Detailed clinical data were also collected. In total, 126 patients with lung cancer participated and received at least one dose of the SARS-CoV-2 vaccine. At 3-6 months after 2nd dose, 99.1% of baseline seronegative patients seroconverted and anti-Spike IgG titers went from a median value of 9.45 to 720 UI/mL. At the 6-9-month time point, titers raised to a median value of 924 UI/mL, and at 12-15 months, after the boost dose, they reached a median value of 3064 UI/mL. Adverse events to the vaccine were mild, and no SARS- CoV-2 infection-related deaths were recorded. In this lung cancer cohort, COVID-19 vaccines were safe and effective irrespective of the systemic anticancer therapy. Most of the patients developed anti-Spike IgG after the second dose, and these titers were maintained over time with low infection and reinfection rates with a mild clinical course.
Borderline ovarian tumors (BOTs) are a subset of epithelial ovarian tumors with low malignant potential but significant risk of relapse (10% to 30%). Unfortunately, surgical prognostic factors for ...BOT relapse have not been clearly identified, probably due to the use of heterogeneous surgical definitions and limited follow-up. The aim of this study was to assess potential relapse risk factors using standard surgical definitions and long follow-up.
All patients diagnosed with BOT for a period of more than 10 years in a single institution were included in the analysis. Complete surgical staging was defined as the set of procedures that follow standard guidelines for staging surgery (except lymphadenectomy), performed either with one or two interventions. Fertility-sparing surgeries that preserved one ovary and the uterus but included all the remaining procedures were classified as complete staging. The relationship between potential risk factors and time to BOT relapse was assessed by log-rank tests corrected for multiple comparisons and Cox regression.
Forty-six patients with a median follow-up of 5.4 years were included, of whom 91.3% had been diagnosed as FIGO stage I disease and 45.7% had received complete staging surgery. Five relapses were detected (10.9%), all of them in women who had been diagnosed with stage I disease and had received incomplete staging surgery. Log-rank tests confirmed the association between incomplete staging surgery and shorter time to BOT relapse.
Complete staging surgery should be considered a cornerstone of BOT treatment in order to minimize the risk of relapse.
Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in ...patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL).
The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy–Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28).
This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were −2.1 (95% confidence interval −2.4, −1.7) for FOSI, −4.6 (−5.6, −3.5) for the EQ-5D-5L index, and −7.9 (−9.6, −6.3) for EQ-VAS.
Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL.
•The impact of ovarian cancer progression on HRQoL was evaluated by comparing HRQoL pre- and post-progression.•A clinically relevant decline in HRQoL was observed following disease progression and for up to 24 weeks during follow-up.•Preservation of HRQoL is an important therapy goal in the maintenance setting and may be achieved with prolonged PFS.
Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently ...arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included 46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval PFI was >6 months after the last cycle of prior platinum) median PFI 12.0 months (interquartile range, IQR, 8.8−17.1). Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6−9.2), and median OS (mOS) of 20.6 months (95% CI 13.6−28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 IQR11.2−22.2 and 10.3 IQR 7.4−14.9 months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5−8.6) versus 7.5 months (95% CI 6.5−10.1, p = 0.03), and 16.4 (95% CI 9.3−27.5) versus 24.2 months (95% CI 17.2−NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.
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