Closing the Evidence Gap: Retrospective and Prospective Strategies to Advance Aripiprazole's Potential Benefits in Patients With Cancer

We would like to commend the authors, O'Callaghan et al., for their insightful contribution published in Pharmacology Research and Perspectives on the potential anticancer properties of aripiprazole (ARI), an atypical antipsychotic (AAP) drug, where they reviewed its mechanisms of action, effects on various cancer types, and translational potential based on in vitro, in vivo, and clinical studies [1]. While preclinical evidence is compelling, the review highlights the critical gap—the very limited number of clinical studies on this topic. Only three population studies exist, and no prospective clinical trials have evaluated ARI as an oncology therapeutic. Challenges include optimizing dosing for anticancer effects without neuropsychiatric side effects and confirming mechanistic targets in humans [1]. ARI is thought to be a promising adjunct to conventional therapies due to its ability to reverse chemoresistance in vitro, as well as its safety profile in humans and its multi-target activity. The review advocates for large-scale cohort studies and phase I/II trials to validate these findings, emphasizing that repurposing ARI could address unmet needs in cancer treatment while accelerating therapeutic development timelines [1]. The purpose of this letter is to draw further attention to the lack of clinical evidence on this topic, propose the potential design of future clinical studies, and highlight potential additional benefits, such as antiemetic and analgesic effects, of AAPs in patients with cancer. The clinical knowledge gap could potentially be addressed by retrospective cohort analyses using oncology and psychiatric pharmacovigilance databases, comparing cancer outcomes (e.g., overall survival, progression-free survival, Response Evaluation Criteria In Solid Tumors [RECIST]-defined therapy response) between patients with sustained ARI exposure and propensity score-matched controls adjusted for prognostic determinants (stage, histology, performance status), risk factors (age, comorbidities, polypharmacy), and treatment confounders (chemotherapy regimens, immunotherapy) [1]. Nested case–control analyses would stratify by cancer type (e.g., pancreatic, breast) and, within each type, by clinically and biologically relevant subtypes, as well as by treatment phase to enable more precise dose–response assessments using pharmacy records [2]. Bias mitigation would involve temporal alignment to diagnosis dates, sensitivity analyses excluding schizophrenia patients to address indication bias, and quantitative adjustment for unmeasured confounders [1]. Mechanistic validation would correlate serum drug levels from routine clinical care with standard tumor biomarkers (Ki-67, p-STAT3) in biobanked specimens and patient-derived organoids, bridging preclinical findings to clinical data. Prospective trials could then test ARI as a chemo-sensitizer in cancers with demonstrated preclinical susceptibility (e.g., pancreatic ductal adenocarcinoma) [1, 2], ensuring biological plausibility while leveraging real-world evidence. This approach systematically addresses confounding, enhances translational relevance, and prioritizes hypothesis-driven validation to inform future randomized controlled trials (RCTs). AAPs overall have been associated with multiple benefits in cancer therapy. Firstly, a RCT published in 2023 demonstrated the positive effect of olanzapine on nutritional status and reduced systemic toxicity from chemotherapy, which could imply better overall survival and improved quality of life [3]. Multiple studies have shown olanzapine's antiemetic effect by acting on multiple receptor types, including 5-HT2, 5-HT3, D2, histamine, and muscarinic receptors [4-6]. Olanzapine has been shown to effectively reduce nausea and vomiting in various clinical settings, such as palliative care, post-anesthesia recovery, and in patients receiving emetogenic chemotherapy, making it a valuable option for managing complex cases of emesis where multiple factors contribute [4-7]. The use of an antipsychotic to control nausea in cancer patients is not unprecedented, as oncology guidelines support the use of haloperidol (a first-generation typical antipsychotic) as a first-line antiemetic therapy [8, 9]. Cancer patients frequently experience significant psychological distress, including stress related to disease management, the emotional impact of diagnosis, and an overall decline in mental health associated with the illness. Hence, it is of great importance that AAPs have been linked with promising efficacy in mitigating neurological and psychological symptoms. In particular, these agents have been associated with low or no risk of triggering extrapyramidal side effects at doses at which an antipsychotic effect is achieved [10], while specific APPs, including ARI, olanzapine, and clozapine, do not increase prolactin levels, or do so minimally [11]. ARI specifically has been linked with reducing hyperprolactinemia, which is reported as an adverse event in patients treated with antipsychotic therapy [12, 13]. AAPs, including olanzapine, risperidone, and ARI, relieve both positive (hallucinations, delusions) and negative symptoms (social withdrawal, anhedonia) of schizophrenia by modulating dopamine and serotonin receptors [14]. These agents also have an atypical binding profile to brain receptors, as well as a greater in vitro affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors than first-generation antipsychotics [15]. Lastly, according to a pooled analysis of two large, placebo-controlled trials, ARI, when used as an add-on treatment to standard antidepressants, significantly improves core symptoms of major depressive disorder, including depressed mood, loss of interest, guilt, and anxiety, as well as secondary symptoms such as insomnia [16]. Thus, AAPs could be efficacious in mitigating psychological distress among patients with cancer. The analgesic effect of AAPs also warrants research. A case series in psychiatric patients with severe comorbidities, including a patient with a brain tumor, suggested that ARI monotherapy may improve nociceptive pain. Importantly, these patients had poor responses to traditional analgesics [17]. It was hypothesized that ARI's modulation of dopamine transmission in pain pathways, particularly in the nigrostriatal region, could contribute to the observed pain reduction, although antagonism of 5-HT2A receptors may also play a role [17]. This was the first report on the potential relationship between ARI and the subjective experience of pain, with only a review discussing the off-label use of AAPs, including ARI, in pain management having been published since then to the best of our knowledge [18]. The above highlights the knowledge gaps around AAP use in cancer treatment. Furthermore, the study by Cho et al. (2025) utilizes cisplatin in vitro and in vivo to assess the chemo-sensitizing effects of ARI on pancreatic cancer cells; however, it is pertinent to note that current clinical guidelines do not typically recommend cisplatin as a first- or second-line treatment option for pancreatic ductal adenocarcinoma [2]. Contemporary treatment protocols favor regimens incorporating agents such as oxaliplatin, irinotecan, 5-fluorouracil, or nab-paclitaxel in combination with gemcitabine, owing to their demonstrated superior efficacy [2]. The relevance of cisplatin in this context, therefore, warrants careful consideration when extrapolating these findings to clinical implementation [2]. Moreover, it is noteworthy that the majority of clinical trials examining ARI were conducted in Asia, which may introduce regional variability. Additionally, these studies exhibited considerable heterogeneity in their methodologies, rendering it challenging to draw definitive conclusions. Consequently, a comprehensive quality assessment would be beneficial to address potential biases and limitations, particularly with respect to participant numbers and trial biases, thereby enhancing the interpretability and generalizability of the findings. Finally, while ARI's mechanisms may align with the hallmarks of cancer [1], substantial clinical evidence is required to support its use as a cancer treatment, particularly considering that the hallmarks of cancer framework are dynamic and subject to revision as new evidence emerges. Despite the positive therapeutic effects of AAPs and ARI in particular, off-label use of ARI requires careful consideration due to its safety profile, which includes risks such as impulse-control disorders, metabolic changes, tardive dyskinesia, and orthostatic hypotension [19]. While its efficacy in off-label indications such as depression and agitation in dementia has been explored, evidence remains insufficient to fully establish the benefit–risk ratio for broader off-label applications [20, 21]. Thus, it is imperative to conduct high-quality randomized RCTs and retrospective studies to establish robust evidence before integrating ARI into routine practice for off-label applications [20]. From an oncological standpoint, given the encouraging outcomes documented in existing literature and considering the disease burden faced by these patients, ARI has promising potential, and comprehensive research is needed to explore the role of AAPs in cancer treatment. Elvira Meni Maria Gkrinia: data curation, investigation, writing – original draft, writing – review and editing. Marin Golčić: data curation, investigation, writing – original draft, writing – review and editing. Andrej Belančić: conceptualization, data curation, investigation, project administration, supervision, writing – original draft, writing – review and editing. The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.