Efficacy and safety of niraparib in patients aged 65 years and older with advanced ovarian cancer: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD). RESULTS: Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups. CONCLUSION: Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age.

Carboplatin plus Paclitaxel in Combination with the Histone Deacetylate Inhibitor, Vorinostat, in Patients with Recurrent Platinum-Sensitive Ovarian Cancer.

Background: This phase II study evaluated the efficacy and safety of the histone deacetylase (HDAC) inhibitor, vorinostat, administered in combination with paclitaxel and carboplatin in patients with platinum sensitive recurrent ovarian cancer. Methods: Women with recurrent platinum-sensitive ovarian, peritoneal, or Fallopian tube carcinoma, a performance status of 0-2, and good overall organ function were eligible. Patients received 6 courses of paclitaxel (175 mg/m2) and carboplatin area under the curve (AUC) of 5.0 mg/mL/min administered via intravenous infusion on day 1 of a 3-week schedule. In addition, patients received vorinostat 400 mg orally once daily on days -4 through 10 of Cycle 1 and days 1 through 14 of each subsequent treatment cycle. The primary endpoints were progression-free survival (PFS) and adverse events. The secondary endpoints were the objective response rate and overall survival. Results: Fifty-five patients were included. CR was obtained in 14 patients (26.4%) and PR in 19 patients (35.8%), resulting in an ORR of 62.2%. Twenty patients (37.7%) had SD. The median duration of response (DoR) was 12.6 (range 6-128) months. The median PFS was 11.6 months (95% CI, 10.3-18.0; p < 0.001). Median OS was 40.6 months (95% Cl, 25.1-56.1). The most common treatment-related adverse events (all grades) were fatigue, anemia, thrombocytopenia, neutropenia, anorexia, nausea, pain, sensory neuropathy, myalgia, stomatitis and diarrhea. Conclusions: Vorinostat combined with carboplatin plus paclitaxel was tolerable and generated significant responses including a long median overall survival in recurrent platinum-sensitive ovarian cancer.

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer.

PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.

Development, implementation and evaluation of patient decision aids supporting shared decision making in women with recurrent ovarian cancer.

Objective: Shared decision making (SDM) and use of patient decision aids (PtDAs) are key components in patient-centered care in relapsed ovarian cancer. This paper describes the development and implementation process of PtDAs into a clinical routine in three departments. Methods: Two PtDAs were developed in collaboration between patients and clinicians. Acceptability and usability of the PtDAs were tested on clinicians and patients using items from the internationally validated questionnaire "Preparation for Decision Making Scale". Results: Ten patients and 15 clinicians participated in the study. Most patients indicated that PtDAs would be helpful as preparation for the decision-making process with the clinicians. Ten (75%) of the clinicians responded that the PtDAs helped the patients to understand the benefits and disadvantages of each treatment option. Generally, the clinicians indicated that they would use SDM if they had a PtDA tailored to the clinical situation. Conclusions: Two PtDAs were systematically developed, tested, and implemented thereby supporting an SDM intervention. The PtDAs are still in use at the participating departments. Innovation: This study was successful in reusing a generic template for a patient decision aid (PtDA) developed at one institution and implemented in two other institutions. This was guided by a well-described systematic development process for PtDAs.

Shared decision making in recurrent ovarian cancer: Implementation of patient decision aids across three departments of oncology in Denmark.

Objective: Patients with relapsed ovarian cancer are offered multiple treatment options. To match treatment with the individual patient's life situation and preferences, healthcare professionals can apply shared decision making (SDM) including patient decision aids (PtDAs).This study aimed to evaluate the implementation of two different PtDAs in consultations with patients suffering from relapsed ovarian cancer. Methods: We analyzed the following data before and after implementation of the PtDAs: 1) observed SDM using the OPTION instrument, 2) physician treatment recommendations, and 3) patients' and physicians' evaluations of SDM in consultations using the CollaboRATE, SDM-Q-9, and SDM-Q-Doc. Results: Significant improvement in observed SDM was found after the implementation (p = 0.002). Improvement of SDM was detected in consultations conducted by physicians reporting more than two hours of SDM-training (p < 0.001), but not when physicians reported less than two hours of SDM-training.No before/after differences in treatment recommendations and in patients' and physicians' evaluations were found. Conclusion: Implementation of PtDAs improved the level of observed SDM. Training of physicians in SDM is necessary for improved SDM practice. Innovation: Discussing oncological treatment options with the use of PtDAs is not standard practice in Denmark. The present study is one of the first Danish studies focusing on how to implement SDM and PtDAs in oncological consultations.

The impact of comprehensive geriatric assessment for optimal treatment of older patients with cancer: A randomized parallel-group clinical trial.

OBJECTIVES: The aim was to investigate if oncologic treatment decision based on G8 screening followed by comprehensive geriatric assessment (CGA) and a multidisciplinary team conference in patients with G8 ≤ 14 was better than treatment decision based on standard assessment. ClinicalTrials.gov Identifier: NCT02671994. MATERIALS AND METHODS: From January 2016 to June 2018, 96 patients with cancer, aged ≥70 years, were included. Patients were randomized to treatment decision based on the oncologist's clinical judgement (control) or based on screening with G8. If G8 > 14 treatment decision was made as in the control group and if G8 ≤ 14, patients were referred to CGA including intervention as needed and treatment decision after a multidisciplinary team conference (MDT). RESULTS: The study was closed early. 47 patients were randomized to the control group and 49 to the intervention group; 28 had a G8 ≤ 14, 24 of whom attended CGA. In the intervention group 48% completed treatment as planned compared to 54% in the control group (p = .208). Thirty-eight percent experienced grade 3-4 toxicity in the control group compared with only 20% in the intervention group (p = .055). Median overall survival (OS) was 14.2 months in the control group and 19.1 months in the intervention group (p = .911). Median progression-free survival (PFS) was 9.0 months in the control group and 7.8 months for the intervention group (p = .838). CONCLUSION: Treatment decision based on G8 screening followed by CGA had no impact on completion rate of planned oncologic treatment, OS or PFS, but resulted in a borderline significant lower incidence of grade 3-4 toxicity.

[Pressurised intraperitoneal aerosol chemotherapy (PIPAC) for the treatment of peritoneal metastases].

Pressurised intraperitoneal aerosol chemotherapy (PIPAC) was introduced in Denmark in 2015. More than 100 Danish patients with peritoneal metastases (PM) have received PIPAC-directed treatment within the PIPAC-OPC1 and PIPAC-OPC2 trials. PIPAC-directed treatment is feasible and safe, and there are no occupational risks for the involved healthcare professionals. An objective tumour response is seen in two out of three patients, and the survival data warrant further evaluation in large-scale randomised trials in patients with PM from different primary tumours.