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Background: Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. Methods: We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Results: Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. Conclusion: The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit. [ABSTRACT FROM AUTHOR]

We sought to quantify exposure to and financial impacts of poly (adenosine diphosphate ribose) polymerase inhibitor (PARPi) treatments for eventually withdrawn ovarian cancer indications. We identified in Optum's deidentified Clinformatics® Data Mart database 1695 patients with ovarian cancer diagnoses who received olaparib, rucaparib, or niraparib between January 2015 and September 2021. We describe PARPi use and out-of-pocket, total healthcare, and PARPi spending among patients with ovarian cancer with 3 or more previous lines of therapy. Of the 1695 patients who received PARPi, 254 were estimated to have been heavily pretreated and exposed to eventually withdrawn indications. Cumulative total medical and pharmacy costs for these patients were $53 392 184; PARPi costs accounted for 34%. Median PARPi cost per patient was $43 347. Cumulative out-of-pocket costs totaled $533 281. Potential patient harm, including financial toxicity, might have been mitigated through more stringent drug approval requirements. • Starting in 2014, 3 poly (adenosine diphosphate ribose) polymerase inhibitors were approved without evidence of overall survival benefit for ovarian cancer treatment of heavily pretreated patients with recurrent disease. Ovarian cancer treatment indications were withdrawn in 2022, after trials demonstrating shorter survival among heavily pretreated patients with recurrent disease. • In addition to potential patient harm from drug exposure, conservative estimates of the number of patients treated with poly (adenosine diphosphate ribose) polymerase inhibitor for the withdrawn indications demonstrated significant financial impact for patients and the healthcare system. • Financial toxicity of Food and Drug Administration cancer drug approvals without evidence of clinical benefit must be considered. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) relieves CD8+ T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+ T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targeting Cbx3 /HP1γ in CD8+ T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity at Lef1 and Il21r. LEF-1 and IL-21R are necessary for Cbx3 /HP1γ-deficient CD8+ effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence of Cbx3 /HP1γ-deficient CD8+ T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4+ Tregs. Thus, CD8+ T cells heightened effector function consequent to Cbx3 /HP1γ deficiency may be distinct from functional reactivation by ICB, implicating Cbx3 /HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors. [ABSTRACT FROM AUTHOR]

The article discusses the importance of cost-effectiveness analyses (CEA) for evaluating health care services related to cervical cancer such as screening tests and treatments, the cost factor involved and the types of resources available in different parts of the world. The article discusses how cost effectiveness of these services can be beneficial in creating and modifying optimal practices. Some of the practices discussed include liquid-based cytology (LBC), human papilloma virus (HPV) testing and the HPV vaccine.

Objective The purpose of this study was to compare primary debulking surgery (PDS) vs neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) among obese patients. Study Design Medical records of patients with a body mass index (BMI) of ≥30 kg/m 2 with ovarian/fallopian tube/primary peritoneal carcinoma between January 2005 and December 2010 were reviewed. Patients were separated by PDS or NACT-IDS. Preoperative characteristics, surgical procedures, and postoperative and oncologic outcomes were compared. Results Of 117 patients, 95 women (81.2%) underwent PDS, and 22 women (18.8%) underwent NACT-IDS. Patients who underwent NACT-IDS were more likely to have stage IV disease (63.6% vs 26.3%; P = .001) and a low surgical complexity score (n = 14; 63.6%). There were no other differences between groups with respect to preoperative characteristics or postoperative morbidity. Compared with the NACT-IDS group, the PDS group had an improved progression-free survival (PFS; 15 vs 11 months; P = .006) and overall survival (OS; 53 vs 32 months; P = .036). Seventy-eight patients (66.7%) had a BMI of 30-34.9 kg/m 2 . Within this subset of obese patients, the PDS group had an improved PFS (15 vs 10 months; P = .011) and OS (58 vs 32 months; P = .033), compared with the NACT-IDS group. Among patients with a BMI of ≥35 kg/m 2 , there was no difference in PFS (14 vs 12 months; P = .316) or OS (38 vs 32 months; P = .640) when the PDS and NACT-IDS groups were compared. Conclusion Patients with a BMI of 30-34.9 kg/m 2 who undergo PDS have improved oncologic outcomes, compared with those women who undergo NACT-IDS. Patients with a BMI of ≥35 kg/m 2 who undergo PDS have similar oncologic outcomes to those who undergo NACT-IDS. Complication rates were similar at all BMIs, regardless of treatment approach. [ABSTRACT FROM AUTHOR]