Prostate cancer remains a major cause of cancer morbidity and mortality and is rising in incidence across the world. Although a succession of randomised controlled trials have improved outcomes across all stages of disease, there remain significant clinical challenges and unmet needs. Repurposed drugs have attracted interest in the treatment of prostate cancer, where a number of agents have been proposed with a range of mechanisms of action suggesting potential benefits. A major advantage of such drugs is the wealth of pre-existing patient safety data typically available, meaning repurposed agents would be expected to have a known and often low toxicity profile and also (as often late in their developmental pathway and hence generic drugs are available) attractive in terms of cost effectiveness. The evidence required for repurposed drugs to become accepted standards of care and enter the treatment formulary however is no less arduous than conventional development pathways, where confirmatory results from randomised phase III trials remain the absolute requirement. Additionally, these efforts are often led by academic trial groups – with challenges then in the steps to licensing that are typically undertaken by industry. To date, despite large scale initiatives, there is a paucity of drugs successfully repurposed in this way. Using examples across the different clinical scenarios we discuss the opportunities and challenges, design and analyses of current phase III trials testing repurposed drugs for the treatment of patients with prostate cancer and highlight where future success may come.

Pancreatic cancer (PC) remains one of the most challenging malignancies to treat. Current therapeutic options are unsatisfactory, and there is an urgent need for more effective and less toxic drugs to improve the dismal prognosis of PC. In recent years, drug repurposing (DR) has emerged as an attractive strategy to identify novel treatments for PC by leveraging existing drugs approved for other indications. Through the use of electronic medical records, Artificial Intelligence, study of metabolic pathways, signalling pathways, and many other approaches, it has become much easier in recent years to identify potential novel uses for old drugs. Although policy, funding and research attention in this area are steadily growing, major challenges to efficient and effective patient-centric DR in PC need to be addressed. These include but are not limited to regulatory, financial and funding barriers and the lack of coordination and collaboration among several sectors and stakeholders. To explore the opportunities and challenges associated with DR in PC, a one-day multi-stakeholder meeting was held on 14th of November 2024 in Brussels, Belgium as part of the REMEDi4ALL project. This meeting provided a platform for researchers, clinicians, industry representatives, funders, regulatory experts, and patient advocates to discuss and propose actions to optimize and accelerate DR in PC. Insights from this meeting support the potential of DR to enhance PC treatment options while highlighting the importance of systemic and supportive changes in the regulatory, policy and funding landscapes, interdisciplinary collaboration, data sharing, and patient involvement in driving therapeutic innovation. This summary highlights key outcomes and recommendations from the meeting in informing future efforts to advance DR initiatives in the context of PC.

Optimising the use of approved drugs requires evidence from post-approval trials that investigate variations of their use. Determining optimal drug use goes beyond the dominant, academic effort to conduct trials to identify effective lower doses of new drugs. Other important therapeutic approaches that use either less, similar, or more drug than the standard dose need testing in clinical trials, to get the most out of these drugs. Trial objectives on survival outcomes vary greatly; some aim for superiority, others for equivalent exposure or non-inferiority. This Personal View aims to inform academic trialists in how to conceive and prioritise questions aimed at determining the optimal use of drugs, taking into account the perspectives of patients, clinicians, and trial funders, to maximise the chances of successful delivery and impact for patients globally.

Ultra-rare sarcomas (URS) and ultra-rare cancers (URC) represent a unique challenge in oncology due to their rarity, heterogeneity, and the severe unmet clinical needs of affected patients. In 2024, the European Medicines Agency (EMA) and the European Organisation for Research and Treatment of Cancer (EORTC) convened two multi-stakeholder workshops, bringing together regulators, clinicians, researchers, and patient advocates. These workshops aimed to explore innovative strategies for treatment development and establish a framework for future collaboration. Key issues were discussed, including the scarcity of biological and clinical data, major barriers in conducting randomized trials, and limited pharmaceutical investment. A key outcome was the unanimous commitment of all stakeholders, including regulatory agencies such as EMA and the U.S. FDA, to work together towards pragmatic solutions. Participants recognized the necessity of flexible regulatory approaches, alternative trial designs, and meaningful endpoints tailored to ultra-rare conditions. The workshops also highlighted the importance of global collaboration, early regulatory engagement, and leveraging existing mechanisms like orphan drug designation and conditional approvals. The discussions emphasized that while scientific rigor must be upheld, regulatory frameworks must adapt to the specific challenges posed by URS. Stakeholders pledged to maintain open dialogue, share expertise, and develop innovative infrastructures to accelerate progress. This collaborative commitment marks a critical step forward in addressing the high unmet needs of URS. By fostering a unified effort among diverse stakeholders, the workshops established a model for advancing treatments in other URC, prioritizing patient outcomes while navigating the complexities of drug development for these challenging diseases.

OBJECTIVE:This study aimed to prospectively evaluate whether hospital case volume is positively associated with both the outcome and the quality of care of uterine corpus cancer in Belgium. METHODS:This was a prospective, observational, registration-based, real-world database study. Hospital case volume was categorized according to the total number of patients treated on average per year: low (<10/y), medium (10-19/y), and high (≥20/y). Adjusting for patient case mix and intra-hospital correlations, logistic and Cox proportional hazards regression were used to test for associations between hospital case volume and a multi-disciplinary set of process and outcome indicators. Sub-group analyses by recurrence risk were performed for overall survival and disease-free survival. RESULTS:In total, 4178 patients diagnosed with a primary cancer of the uterine corpus between 2012 and 2016 in Belgium were included. Compared with patients treated in high-volume hospitals, patients treated in low-volume hospitals were more likely to die of any cause within 5 years after diagnosis (adjusted hazard ratio 1.37, p < .01), as were patients treated in medium-volume hospitals (adjusted hazard ratio 1.18, p < .05). Similar results were observed in the sub-group analyses, but only among patients with high-intermediate-risk and high-risk disease. In contrast, hazards for disease-free survival did not differ by hospital case volume, neither in the total study population nor in the sub-group analyses by recurrence risk. Furthermore, analysis of the process indicators showed that patients treated in low- and medium-volume hospitals were less likely to receive multiple guideline-recommended procedures compared with those treated in high-volume hospitals, including minimally invasive surgery, surgical lymph node staging, staging omentectomy, and adjuvant chemotherapy. CONCLUSIONS:On average, increased hospital case volume was positively associated with improved overall survival and quality of care, supporting centralization of uterine corpus cancer care into high-volume reference centers in Belgium.

Developing new drugs or generating evidence for existing drugs in new indications for ultra -rare cancers is complex and carries a high -risk of failure. This gets even harder in ultra -rare tumours, which have an annual incidence of 1 per 1,000,000 population or less. Here, we illustrate the problem of adequate evidence generation in ultra -rare tumours, using Alveolar Soft -Part Sarcomas (ASPS) - an ultra -rare sarcoma newly diagnosed in approximately 60 persons a year in the European Union - as an exemplar case showing challenges in development despite being potentially relevant for classes of agents. We discuss some possible approaches for addressing such challenges, especially focussing on constructive collaboration between academic groups, patients and advocates, drug manufacturers, and regulators to optimise drug development in ultra -rare cancers. This article, written by various European stakeholders, proposes a way forward to ultimately get better options for patients with ultra -rare cancers.

Our international team highlights issues with efficacy reports in several studies on DMG with the new drug ONC201.

Pharmaceuticals are a major cost driver of cancer treatment, and access to many agents with potential benefit is limited because of their high cost, both for individual patients and for health services. The World Health Organization list of essential medicines 1 World Health Organization Model List of Essential Medicines – 22nd List, 2021. Geneva: World Health Organization; 2021 (WHO/MHP/HPS/EML/2021.02). Google Scholar includes ‘the most efficacious, safe and cost–effective medicines’ to meet the needs of a basic health care system. The 2021 list does not include several molecular targeted agents (MTAs) or immunomodulators that have been shown to improve substantially the survival of people with cancer. New drugs are marketed typically at prices of ≥US $10 000 per month; thus they cannot be afforded in low- and middle-income countries (LMICs) or by patients lacking health insurance, and they limit available resources for other health care delivery in all countries. A recent study from India showed that only 3% of patients with lung or head and neck cancers who might benefit from immunotherapy, a standard of care in high-income countries (HICs), were able to receive it. 2 Patil V. Abraham G. Ravikrishna M. et al. Retrospective analysis: checkpoint inhibitor accessibility for thoracic and head and neck cancers and factors influencing it in a tertiary centre in India. Ecancermedicalscience. 2022; 16: 1464 Crossref PubMed Scopus (2) Google Scholar Older listed drugs, such as trastuzumab, which improves survival (and the probability of cure) for women with HER-2-positive breast cancer, are not available to many women in LMICs. 3 Ghosh J. Gupta S. Desai S. et al. Estrogen, progesterone and HER2 receptor expression in breast tumors of patients, and their usage of HER2-targeted therapy, in a tertiary care centre in India. Indian J Cancer. 2011; 48: 391-396 Crossref PubMed Scopus (76) Google Scholar Many anticancer drugs were developed through research funded in part by government and/or charitable sources, but most clinical trials are sponsored by pharmaceutical companies, and drugs are launched at high price to maximize profit, and to putatively recoup the cost of development of both successful and failed drugs—as opposed to pricing based on value. By contrast, manufacturing, research and development costs of most life-prolonging drugs are a small fraction of their market price. 4 Prasad V. Mailankody S. Research and development spending to bring a single cancer drug to market and revenues after approval. JAMA Intern Med. 2017; 177: 1569-1575 Crossref PubMed Scopus (281) Google Scholar

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Objectives. To investigate the practice patterns and quality of care for uterine cancer on a national level in Belgium, including trends in practice over the period 2012-2016.Methods. Quality indicators were measured using the EFFectiveness of Endometrial Cancer Treatment (EF-FECT) database. Multivariable logistic mixed regression was used to test for associations between the quality indicators and year of diagnosis, adjusted for potential confounders and intra-cluster correlations.Results. The EFFECT database includes 4178 patients diagnosed with uterine cancer in the period 2012-2016. Minimally invasive surgery (laparoscopic or robotic-assisted) was applied in 61.6% of patients who had surgery for clinical stage I endometrial carcinoma (EC), increasing from 52.9% in 2012 to 66.4% in 2016. At least pelvic lymph node staging was performed in 69.0% of patients with clinical stage I, high-grade EC; and in 63.9% of patients with clinical stage I-II serous carcinoma, clear cell carcinoma or carcinosarcoma. The latter increased from 48.8% in 2012 to 77.2% in 2016. Adjuvant radiotherapy (external beam and/or brachytherapy) was offered to 33.5% of patients who had surgery without lymph node staging for pathological stage I EC at high-intermediate or high risk of recurrence. Adjuvant chemotherapy was administered to 64.4% of patients with pathological stage III-IVA EC.Conclusions. Study results indicate an overall good quality of care for patients with uterine cancer in Belgium. Treatment areas with potential room for improvement include the use of minimally invasive surgery, comprehensive surgical staging and adjuvant therapy, which confirms the remaining controversies in uterine cancer treatment and the need for further research.(c) 2023 Elsevier Inc. All rights reserved.

Introduction/Background This study aims to examine the treatment patterns and quality of care for endometrial carcinoma (EC) in Belgium, including trends in practice over time. Methodology To study patterns and quality of care, quality indicators were developed, and the data necessary to measure these indicators was prospectively collected and stored in the EFFectiveness of Endometrial Cancer Treatment (EFFECT) database by the Belgian Cancer Registry (BCR) using an online registration module. To study trends over time, multivariable logistic mixed regression was used to estimate risk-adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between the quality indicators and year of diagnosis. Results The EFFECT database covers detailed information on the care provided to 4178 patients diagnosed with corpus uteri cancer in Belgium between 2012 and 2016. First, 97.6% (n=4077) of all patients were discussed in at least one multidisciplinary team meeting, which increased from 96.4% (n=726) in 2012 to 98.5% (n=767) in 2016 (aOR=2.95; 95% CI=1.43–6.08). Second, minimally invasive (laparoscopic or robotic) surgery was used in 61.6% (n=1359) of all patients who had surgery for stage I EC, increasing from 52.9% (n=192) in 2012 to 66.4% (n=285) in 2016 (aOR=1.99; 95% CI=1.35–2.95). At least pelvic lymphadenectomy was performed in 69.0% (n=363) of all patients with stage I, high-grade (type I grade 3 or type II) EC. Third, adjuvant radiotherapy was administered to 33.5% (n=107) of all patients who received surgery (without lymph node staging) for stage I EC at high-intermediate or high risk of recurrence. Adjuvant chemotherapy was applied in 64.4% (n=270) of all patients who had surgery for locally advanced (stage III-IVA) EC. Conclusion This study suggests that improvements are needed in both the surgical and adjuvant treatment of EC in Belgium. However, some improvements were already observed over the period 2012–2016, and clinical practice may have further advanced since. Disclosures Funded by The Anticancer Fund and Kom op tegen Kanker.

Medicine regulators, such as the UK's Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA), have statutory duties to ensure the safety, quality, and efficacy of medicines, medical devices, and blood products. To ensure these duties are met, and to safeguard the health of the population, drug regulators are alerted to safety signals for licensed medicines. Pharmacovigilance systems monitor and act on emerging data, regardless of provenance (ie, whether the data come from company-sponsored studies or from non-company sources). 1 European Medicines AgencyHeads of Medicines AgenciesGuideline on good pharmacovigilance practices (GVP): module VI—collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev 2). https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-submission-reports_en.pdfDate: July 28, 2017 Date accessed: February 2, 2023 Google Scholar However, this effective monitoring process does not capture data showing the efficacy of new medical uses for existing medicines. We propose that regulators institute a drug evidence watch process to track emerging data showing the efficacy of drugs in new indications. Given that pharmacovigilance can lead to label changes, we suggest that this drug evidence watch includes a form of efficacy vigilance that could lead to label extension.

Immune checkpoint blockers (ICB) have transformed the treatment landscape of many advanced cancers, and attention naturally shifts to the adjuvant setting. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved four anti-PD-(L)1 antibodies (atezolizumab, durvalumab, nivolumab, and pembrolizumab) in a total of nine adjuvant indications, as of October 2022 (Table 1) . The cost of these drugs is in excess of $150,000 a year for all ICB listed (e.g. US list price of 200 mg pembrolizumab is $20,948). Table 1List of approved immune checkpoint blockers as (neo)adjuvant treatment as of October 2022. Drug Cancer FDA approval EMA approval Dose and schedule on the drug's label (number of administration) First schedule Other schedule(s) Pembrolizumab Melanoma Yes Yes 200 mg Q3W (18) 400 mg Q6W (9) Pembrolizumab TNBC Yes Yes 200 mg Q3W (8 a neoadjuvant; NSCLC: non-small cell lung cancer, RCC; renal cell carcinoma, TNBC: triple-negative breast cancer. +9) 400 mg Q6W (4 a neoadjuvant; NSCLC: non-small cell lung cancer, RCC; renal cell carcinoma, TNBC: triple-negative breast cancer. +4) Pembrolizumab RCC Yes Yes 200 mg Q3W (18) 400 mg Q6W (9) Nivolumab Melanoma Yes Yes 240 mg Q2W (26) 480 mg Q4W (13) Nivolumab Urothelial Yes Yes 240 mg Q2W (26) 480 Mg Q4W (13) Nivolumab Oesophageal Yes Yes 240 mg Q2W (26) 480 mg Q4W (13) Nivolumab NSCLC Yes Yes 360 mg Q3W (3 a neoadjuvant; NSCLC: non-small cell lung cancer, RCC; renal cell carcinoma, TNBC: triple-negative breast cancer. ) / Atezolizumab NSCLC Yes Yes 840 mg Q2W (26) 1200 mg Q3W (17) or 1680 mg Q4W (13) Durvalumab NSCLC Yes Yes 10 mg/kg Q2W (26) 1500 mg Q4W (13) a neoadjuvant; NSCLC: non-small cell lung cancer, RCC; renal cell carcinoma, TNBC: triple-negative breast cancer. Open table in a new tab

BACKGROUND:With the aim of obtaining more uniformity and quality in the treatment of corpus uteri cancer in Belgium, the EFFECT project has prospectively collected detailed information on the real-world clinical care offered to 4063 Belgian women with primary corpus uteri cancer. However, as data was collected on a voluntary basis, data may be incomplete and biased. Therefore, this study aimed to assess the completeness and potential selection bias of the EFFECT database.METHODS:Five databases were deterministically coupled by use of the patient's national social security number. Participation bias was assessed by identifying characteristics associated with hospital participation in EFFECT, if any. Registration bias was assessed by identifying patient, tumor and treatment characteristics associated with patient registration by participating hospitals, if any. Uni- and multivariable logistic regression were applied.RESULTS:EFFECT covers 56% of all Belgian women diagnosed with primary corpus uteri cancer between 2012 and 2016. These women were registered by 54% of hospitals, which submitted a median of 86% of their patients. Participation of hospitals was found to be biased: low-volume and Walloon-region centers were less likely to participate. Registration of patients by participating hospitals was found to be biased: patients with a less favorable risk profile, with missing data for several clinical-pathological risk factors, that did not undergo curative surgery, and were not discussed in a multidisciplinary tumor board were less likely to be registered.CONCLUSIONS:Due to its voluntary nature, the EFFECT database suffers from a selection bias, both in terms of the hospitals choosing to participate and the patients being included by participating institutions. This study, therefore, highlights the importance of assessing the selection bias that may be present in any study that voluntarily collects clinical data not otherwise routinely collected. Nevertheless, the EFFECT database covers detailed information on the real-world clinical care offered to 56% of all Belgian women diagnosed with corpus uteri cancer between 2012 and 2016, and may therefore act as a powerful tool for measuring and improving the quality of corpus uteri cancer care in Belgium.

BACKGROUND:Once a drug gets FDA approved, researchers often attempt to discover new applications in different indications. The clinical impact of such post-approval activities is uncertain. We aimed to compare the clinical impact of research efforts started after approval with those started before for cancer drugs.METHODS:We used Drugs@FDA to perform a retrospective cohort study of secondary approvals for cancer drugs that were initially FDA approved between 2005 and 2017. Clinicaltrials.gov was used to identify the beginning of each research trajectory that resulted in a secondary FDA approval. Each trajectory was classified as pre- or post-approval depending on if it was initiated before or after initial drug licensure. Clinical impact was assessed by comparing secondary approvals and NCCN off-label recommendations deriving from pre- vs. post-approval trajectories, pooled effect sizes, incidence, and level of evidence.RESULTS:We identified 77 broad secondary approvals, 60 of which had at least 6 years follow-up. Of these, 9 (15%) resulted from post-approval trajectories, a proportion that is significantly lower than would be expected if the timing of research didn't impact approval (McNemar's test p = 0.001). Compared to pre-approval trajectories, approvals resulting from post-approval trajectories were for cancers with lower mean incidence (6.11 vs 14.83, p = 0.006) and were based on pivotal trials with smaller pooled effect sizes (0.69 vs 0.57, p = 0.02) that were less likely to be randomized (38.5% vs 64.1%, p = 0.145). We identified 69 NCCN off-label recommendations. The proportion stemming from post-approval trajectories was similar to that for pre-approval (56.5% vs. 43.5%). However, recommendations from post-approval trajectories were significantly more likely to involve rare diseases (76.7% vs 51.4%, p = 0.019) and nonsignificantly less likely to be based on level 1 evidence (11.6% vs 22.9%, p = 0.309).CONCLUSION:Secondary FDA approvals are less likely to result from post-approval trajectories and tend to be less impactful compared to approvals originating from research started before first FDA licensure. However, post-approval trajectories may be as likely to lead to NCCN recommendations for off-label use. Limitations of this work include our use of indirect measures of impact and limited follow-up time for trajectories. Our study protocol was pre-registered (https://osf.io/5g3jw/).

Timely and comprehensive updating of treatment guidelines remains a challenge and necessity in medical oncology. Herein we discuss our assessment of how trial results with four off-patent drugs have been considered for integration into major guidelines in the absence of a commercial sponsor, in which we found reasons for concern.

OBJECTIVE:Drug repurposing is an alternative development pathway that utilizes the properties of drugs approved for other diseases and builds on available safety and pharmacological data to develop the drug as a potential treatment for other diseases. A literature-based approach was performed to identify drug repurposing opportunities in cervical cancer to inform future research and trials. METHODS:We queried PubMed for each drug included in two databases (ReDO_DB and CDcervix_DB, which include 300+ non-cancer drugs and 200+ cancer drugs not used in cervical cancer, respectively) and manually assessed all abstracts for relevance and activity in cervix cancer, and type of evidence. Subsequently, we also performed a search of clinical trial databases where we generated a list of registered trials in cervical cancer with all drugs from our databases. RESULTS:Of the 534 drugs from both databases, 174 (33%) had at least one relevant abstract or registered trial in cervical cancer. 94 (18%) drugs had at least human data available, and 52 (10%) drugs were evaluated in registered trials. To prioritize drugs to consider for future trials, all 174 drugs were further assessed for strength of scientific rationale, feasibility for integration in cervical cancer standard of care, evidence of radiosensitization, and potential mechanism of action. Out of the 174 drugs, 38 (22%) potential drug candidates were selected. CONCLUSION:This study resulted in a list of candidate drugs for potential evaluation in cervical cancer. Many drugs might warrant additional (pre)clinical investigation, which could be done in a coordinated manner using platform trials.

AbstractBackgroundThe dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide—version 3—(CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3.MethodsTen adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3–4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle.ResultsOne patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%.ConclusionsCUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.