Tito Fojo

Supplemental Table 1. Specific Medications

Background:Neural regulation contributes to pancreatic ductal adenocarcinoma (PDAC) development, but effects of neural-targeting medications on presentation or outcomes remain unclear. Methods:We conducted a retrospective study using the Veterans Affairs (VA) Corporate Data Warehouse (CDW) to identify patients with pancreatic cancer (2000–2020). Exposure to β-blockers, cholinergics, or statins was defined by active prescriptions within 6 months before or 1 month after diagnosis. Outcomes included histologic subtype, stage, and overall survival (OS). Propensity score matching was performed for each medication class, with survival assessed using Kaplan–Meier and Cox regression models. Results:Among 7,578 veterans with pancreatic cancer, 76% had adenocarcinoma and 60% presented with stage IV disease. β-Blocker use was associated with lower odds of advanced stage [odds ratio (OR), 0.55; 95% confidence interval (CI), 0.5–0.63; P < 0.0001] and improved OS [hazard ratio (HR), 0.89; 95% CI, 0.84–0.95; P < 0.0001]. Cholinergic agonist use was associated with reduced likelihood of adenocarcinoma histology (OR, 0.64; 95% CI, 0.41–1.01; P = 0.051) and advanced stage (OR, 0.53; 95% CI, 0.34–0.85; P = <0.0001) but not OS. Statin use was associated with adenocarcinoma histology (OR, 1.24; 95% CI, 1.09–1.43; P = 0.002) and lower odds of advanced stage (OR, 0.77; 95% CI, 0.68–0.88; P = <0.0001). Conclusions:β-Blockers were associated with earlier stage and improved survival. Cholinergic agonists and statins were associated with earlier stage. Cholinergic agonists were linked to lower likelihood of adenocarcinoma histology, whereas statins were linked to higher likelihood. These findings suggest that neural and metabolic pathways may shape early PDAC biology. Impact:Autonomic and metabolic pathways may influence PDAC biology. β-Blockers merit mechanistic and clinical evaluation as adjunctive therapies.

Supplemental Table 2. Sensitivity Analysis

In the United States the Food and Drug Administration (FDA), and in Europe, the European Medicines Agency (EMA) are responsible for regulatory approvals of anti-cancer therapeutics. We examined regulatory approvals by both agencies in the period between 2014 and 2025 and compared immunotherapy and non-immunotherapy approvals for the treatment of cancer. We asked whether the approvals were similar in terms of trial size, endpoints, and development time. We present the data based on the FDA approvals given that the US agency has approved some therapies either rejected by or yet to be approved by the EMA. Beginning with the approval of pembrolizumab for melanoma in 2014 through early 2025 we identified 143 immunotherapy and 211 non-immunotherapy approvals. In the first few years the time to approvals of immunotherapies was markedly less but over time the duration has approached that of non-immunotherapies – with durations of 2079 and 2357 days in 2024/2025 due largely to a median trial size of 461 and 698 participants. Surrogate endpoints have overwhelmed overall survival as the primary endpoint for approval, and we find that with non-immunotherapies only a median of 60% of the benefit predicted from progression/disease/recurrence/event-free survivals translates to overall survival, significantly less than the 99% of the surrogate benefit translated to overall survival for immunotherapies. While the FDA and EMA approval portfolios are very similar, the EMA is on the whole more skeptical/conservative in its approvals. The last decade has seen substantial advances, but much remains to be accomplished against a formidable foe. The size and duration of trials need to be addressed and meaningfully reduced and the validity of surrogates defended.

Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms originating from chromaffin cells that express somatostatin receptors (SSTRs) and may therefore be susceptible to somatostatin analogue therapy. Despite this biological rationale, prospective evidence supporting the antiproliferative activity of somatostatin analogues in PPGL is limited. We conducted a multicenter phase 2 clinical trial to assess the efficacy and safety of lanreotide in patients with advanced or metastatic PPGL. [ LAMPARA, NCT03946527 ] Methods: Patients with advanced or metastatic PPGL and evidence of recent disease progression received lanreotide depot/autogel 120 mg subcutaneously every 4 weeks. Treatment was planned for 52 weeks with an option to continue for an additional 52 weeks. Endpoints included overall survival (OS), progression-free survival (PFS), and response according to RECIST. Serum chromogranin A (CgA) was evaluated as an exploratory biomarker. A tumor growth rate analysis was planned to allow comparison with data from the CLARINET trial in gastroenteropancreatic NETs. Results: Eighteen patients (median age 42 years; range 28-77) across three centers participated; 78% carried SDHx mutations. Lanreotide was well tolerated with predominantly grade 1-2 adverse events and no treatment discontinuations due to toxicity. The most common treatment-emergent adverse events were diarrhea (67%), injection-site reaction (44%), constipation (39%), fatigue (39%), and abdominal pain (39%). Serious adverse events were reported in four patients and were assessed as not related or unlikely related to lanreotide. All 18 patients had at least one recorded post-baseline tumor assessment. Two partial responses were recorded during extended follow-up. At approximately 1 year, disease stabilization was observed in 11 of 13 patients (85%) with an available assessment, while two patients (15%) had progressive disease. Biomarker analysis showed substantial variability in serum CgA values. Tumor growth rate analysis revealed a median growth rate of 0.00124/day (tumor doubling time 559 days), comparable in order of magnitude to the rate of 0.00046/day observed in 83 lanreotide-treated patients in CLARINET, and consistent with a median PFS ≥2 years. Conclusions: Lanreotide exhibits promising antiproliferative activity in PPGL, with a favorable safety profile and extended periods of disease stabilization. These findings support the consideration of SSAs as an option in managing SSTR-positive PPGLs, delaying more aggressive treatments until disease progression mandates escalation.

Purpose: Metastatic pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine malignancies with limited systemic treatment options. Although vascular endothelial growth factor (VEGF) pathway inhibition has demonstrated activity in metastatic PPGL, prospective data evaluating selective VEGF receptor inhibition are limited. Axitinib is a potent, selective inhibitor of VEGFR-1, -2, and -3. We evaluated the efficacy and safety of axitinib in patients with progressive metastatic PPGL. Methods: Patients with progressive metastatic or unresectable PPGL were enrolled in a prospective, open-label, single-arm, phase II study ( NCT03839498 ). Eligible patients had measurable disease by RECIST version 1.1 and no prior treatment with a tyrosine kinase inhibitor. Axitinib was administered orally at an initial dose of 5 mg twice daily with protocol-defined dose modifications based on tolerability. The primary end points were objective response rate (ORR) and progression-free survival (PFS). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Results: Nineteen patients were enrolled, and 17 received study treatment and were evaluable for efficacy and safety. Six patients achieved a confirmed partial response, with an ORR of 35.3%. Median progression-free survival was 7.9 months (95% CI, 6.1-16.8 months), median duration of response was 7.4 months, median duration of treatment was 9.5 months, and median overall survival was 29 months. Hypertension, the most common treatment-related adverse event, occurred in 79% of patients, was effectively managed with antihypertensive therapy and dose modifications. Other common treatment-related adverse events included fatigue, diarrhea, oral mucositis, and palmar-plantar erythrodysesthesia. No patient permanently discontinued treatment because of treatment-related toxicity. Conclusions: Axitinib demonstrated clinically meaningful antitumor activity in patients with progressive metastatic PPGL with a safety profile consistent with VEGF pathway inhibition and manageable with supportive care and dose modification. The observed activity was comparable to that reported with other VEGF-targeted therapies, including sunitinib. These findings support axitinib as a potential treatment option for patients with metastatic PPGL and warrant further evaluation.

Background: Neural regulation contributes to pancreatic ductal adenocarcinoma (PDAC) development, but effects of neural-targeting medications on presentation or outcomes remain unclear. Methods: We conducted a retrospective study using the Veterans Affairs (VA) Corporate Data Warehouse (CDW) to identify patients with pancreatic cancer (2000–2020). Exposure to β-blockers, cholinergics, or statins was defined by active prescriptions within 6 months before or 1 month after diagnosis. Outcomes included histologic subtype, stage, and overall survival (OS). Propensity score matching was performed for each medication class, with survival assessed using Kaplan–Meier and Cox regression models. Results: Among 7,578 veterans with pancreatic cancer, 76% had adenocarcinoma and 60% presented with stage IV disease. β-Blocker use was associated with lower odds of advanced stage [odds ratio (OR), 0.55; 95% confidence interval (CI), 0.5–0.63; P < 0.0001] and improved OS [hazard ratio (HR), 0.89; 95% CI, 0.84–0.95; P < 0.0001]. Cholinergic agonist use was associated with reduced likelihood of adenocarcinoma histology (OR, 0.64; 95% CI, 0.41–1.01; P = 0.051) and advanced stage (OR, 0.53; 95% CI, 0.34–0.85; P = <0.0001) but not OS. Statin use was associated with adenocarcinoma histology (OR, 1.24; 95% CI, 1.09–1.43; P = 0.002) and lower odds of advanced stage (OR, 0.77; 95% CI, 0.68–0.88; P = <0.0001). Conclusions: β-Blockers were associated with earlier stage and improved survival. Cholinergic agonists and statins were associated with earlier stage. Cholinergic agonists were linked to lower likelihood of adenocarcinoma histology, whereas statins were linked to higher likelihood. These findings suggest that neural and metabolic pathways may shape early PDAC biology. Impact: Autonomic and metabolic pathways may influence PDAC biology. β-Blockers merit mechanistic and clinical evaluation as adjunctive therapies.

Importance: The choice of first line hormonal therapy in metastatic hormone-sensitive prostate cancer (mHSPC) is often based on comorbidities or physician preference due to the lack of data comparing abiraterone and enzalutamide in clinical trials and in clinical practice settings, especially in African American patients. Objective: To compare clinical outcomes in patients with mHSPC treated with abiraterone acetate or enzalutamide. Design, Setting, and Participants: This cohort study included all patients with mHSPC diagnoses in the US Veterans Affairs Health Care system who initiated abiraterone or enzalutamide between July 2017 and April 2023. Data were analyzed from April 2024 to March 2025. Exposures: Receipt of abiraterone acetate or enzalutamide. Main outcomes and measures: Drug outcomes were established by estimating rates of tumor growth ( g -rates) using prostate-specific antigen (PSA) values while receiving therapy and measuring overall survival (OS). Two different matching analyses were performed: inverse probability weighting (IPW) and 1:1 exact matching. Results: A total of 1258 patients (median [IQR] age, 73 [69-79] years; 314 [25.0%] African American, 857 [68.1%] White, and 87 [6.9%] with other or unknown race) who received abiraterone and 311 patients (median [IQR] age, 74 [69-79] years; 84 [27.0%] African American, 207 [66.6%] White, and 20 [6.4%] with other or unknown race) who received enzalutamide were included. In the unweighted analysis, the abiraterone cohort had median (IQR) g -rate of 0.000137/d (0.000094-0.001519) and the enzalutamide cohort, 0.000137/d (0.000098-0.001815); median (IQR) OS was 36.2 (32.8-38.8) months for abiraterone and 36.2 (34.1-40.5) months for enzalutamide, with a median (IQR) follow-up of 28.7 (15.6-45.6) and 30.8 (16.1-39.1) months, respectively. In IPW analysis, using abiraterone as reference, the weighted median OS was comparable between abiraterone and enzalutamide in the full cohort (36.2; 95% CI, 32.8-38.8 vs 35.5; 95 % CI, 32.9-40.4 months; hazard ratio [HR], 1.09; 95% CI, 0.92-1.30; P = .32), African American veterans (39.7; 95% CI, 34.3-46.6 vs 40.3; 95% CI, 34.3-not reached months; HR, 0.98; 95% CI, 0.72-1.34; P = .90) and those with cardiovascular disease (31.5; 95% CI, 28.1-35.5 vs 35.0; 95% CI, 30.7-38.9; HR, 1.12; 95% CI, 0.91-1.37; P = .30). In 1:1 matched analysis, both the abiraterone and enzalutamide groups had 279 patients with 63 (23%) who were African American; these patients had a median (IQR) follow-up of 27.3 (15.3-40.8) and 31.1 (16.8-39.9) months, respectively. The 1:1 matched cohort consisted of 158 patients (57%) in each group with an initial Gleason score of 8 or higher, and 224 patients (80%) in each group with a PSA value of 50 ng/mL or higher at treatment initiation. For the 1:1 matched cohort and its subgroups of African American patients, patients with Gleason scores of 8 or higher, and patients with a starting PSA level of 50 ng/mL or higher, no statistically significant difference in median g -rate and OS was observed. Conclusions and Relevance: This cohort study found that abiraterone and enzalutamide had comparable outcomes in a first-line mHSPC setting, with similar g -rates and OS in both White and African American patients. There were no differences in survival or g -rate between treatment based on race, comorbidities, and prostate cancer features, including Gleason score, PSA, and volume of disease.