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Targeted composite value-based endpoints in platinum-sensitive recurrent ovarian cancer.

ABSTRACT: OBJECTIVES:FDA-approved treatments for platinum-sensitive recurrent ovarian cancer (PSROC) include bevacizumab and PARP inhibitors (PARPi); clinical decisions regarding therapy must be made prior to initiating chemotherapy. Using the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) value frameworks, we assessed relative values of concurrent/maintenance biologic therapies in PSROC. METHODS:Value scores were calculated for key maintenance therapies based on randomized controlled trials: bevacizumab (OCEANS, GOG 213); olaparib (Study 19, SOLO2); niraparib (NOVA); rucaparib (ARIEL3). Personalized value scorecards were constructed for patients with germline/somatic-BRCA mutations, homologous recombination deficiency (HRD), and wild-type BRCA (wBRCA). ASCO value scores assess clinical benefit, toxicity, long-term survival, symptom palliation, treatment-free interval, and quality of life (QOL). ESMO value scores assess clinical benefit, toxicity, and QOL. RESULTS:ASCO scores were highest for maintenance PARPi in germline/somatic-BRCA mutation cohorts: olaparib (SOLO2)?=?47, (Study 19)?=?62; niraparib?=?50; rucaparib?=?54. HRD cohorts had slightly lower scores: niraparib?=?46; rucaparib?=?37. wBRCA cohorts had the lowest scores: niraparib?=?26; rucaparib?=?26; and olaparib (Study 19)?=?32, as did patients receiving bevacizumab (OCEANS)?=?35, (GOG 213)?=?26. ESMO scores demonstrated high-value for maintenance PARPi in germline/somatic-BRCA mutation cohorts and low-value for bevacizumab and PARPi in wBRCA cohorts. CONCLUSIONS:The value of maintenance PARPi therapy depends heavily on BRCA status, with the highest value scores in germline/somatic-BRCA mutation cohorts. Personalized value scorecards provide a visual aid to assess the harm-benefit balance of maintenance PARPi for PSROC.

SUBMITTER: Foote JR

PROVIDER: S-EPMC7522787 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Targeted composite value-based endpoints in platinum-sensitive recurrent ovarian cancer.

Foote Jonathan R JR Secord Angeles Alvarez AA Liang Margaret I MI Ehrisman Jessie A JA Cohn David E DE Jewell Elizabeth E Havrilesky Laura J LJ

Gynecologic oncology 20190301 3

<h4>Objectives</h4>FDA-approved treatments for platinum-sensitive recurrent ovarian cancer (PSROC) include bevacizumab and PARP inhibitors (PARPi); clinical decisions regarding therapy must be made prior to initiating chemotherapy. Using the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) value frameworks, we assessed relative values of concurrent/maintenance biologic therapies in PSROC.<h4>Methods</h4>Value scores were calculated for key maintenance ...[more]

PMID: 30876487

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Project description:PurposePlatinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy.Patients and methodsNRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs).ResultsBetween February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed.ConclusionCombination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.

Project description:BackgroundAlthough rechallenge with platinum-based chemotherapy is effective for most platinum-sensitive recurrent ovarian cancer (ROC) patients, there is still a subset of patients who have no responses to the standard care. Overcoming multidrug resistance (MDR) is a top priority in oncology clinics, but it remains intricate. It is difficult for clinicians to manage unretractable ROC when conventional therapy yields no results. The rational and effective use of immunotherapy will contribute to the clinical benefit of these patients, especially in patients without approved immunotherapy biomarkers. Here we present a case of successful secondary radical surgery for unretractable metastatic MDR ROC by immunotherapy based on her immune-infiltrating tumor microenvironment signatures.Case descriptionA 57-year-old woman, diagnosed with IC2 stage high-grade serous ovarian cancer in 2015, underwent immediate ultra-radical cytoreductive surgery followed by 6 cycles of platinum-containing adjuvant chemotherapy. After nearly 37 months of disease-free status, the woman complained of spontaneous pain from the right subcostal margin for 1 month and was diagnosed with ROC accompanied by multiple unretractable colorectal and hepatic metastases. Standard chemotherapies were ineffective and quickly resulted in disease progression and grade IV myelosuppression followed impaired gastrointestinal function. Notably, after standard chemotherapy, the patient was tested negative for all immune biomarkers, but multiple fluorescence immunohistochemistry indicated that her tumor tissue was significantly infiltrated with the cluster of differentiation 8 (CD8) T cells and natural killer (NK) cells, implying potential benefits of immunotherapy. Then changed to 3 cycles of intravenous pembrolizumab, the main pelvic tumor and hepatic metastases showed significant shrinkage and achieved partial response, but the disease progressed after 8.7 months. Subsequently, arterial perfusion with pembrolizumab was performed combined with the chemotherapy. A comfortingly partial response was achieved again that enabled the patient to successfully undergo a secondary radical surgery for colorectal and liver metastases. Since that time the patient's postoperative course has been favorable, and she remains disease-free at present for at least 17 months.ConclusionsImmune infiltration signatures of the tumor microenvironment could serve as an indication for immunotherapy in patients with unretractable platinum-sensitive ROC with MDR. In addition, the introduction of immunotherapy might bring some degree of chemotherapy resensitization.

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Targeted composite value-based endpoints in platinum-sensitive recurrent ovarian cancer.

Publications

Targeted composite value-based endpoints in platinum-sensitive recurrent ovarian cancer.

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