Association between low total serum testosterone and body mass index in Australian survivors of testicular cancer: a retrospective analysis.

BACKGROUND: Primary hypogonadism is a recognised complication in survivors of testicular cancer. However, secondary hypogonadism can result from other causes that suppress the hypothalamic-pituitary axis, including obesity, high dose glucocorticoids, chronic end organ failure, and diabetes. The aim of this study was to explore low total serum testosterone in Australian survivors of testicular cancer and examine associations with body mass index, age, and prior chemotherapy use. METHODS: Clinical data including height, weight, diagnosis, treatment, and hormonal evaluations during follow-up were extracted from the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Chemocog study (2007-2012), accompanied by data from two Australian, high-volume testicular cancer centres included in the iTestis testicular cancer registry (2012-2019). Low testosterone was defined by a serum concentration of testosterone (T) < 10 nmol/L, and was classified as primary by a serum concentration of luteinising hormone (LH) > 8 IU/L, otherwise as secondary. RESULTS: Two hundred eighty-five individuals with either stage 1 or advanced testicular cancer were included. Of these, 105 (37%) were treated with orchidectomy and chemotherapy. Forty-nine (17%) met criteria for low testosterone during follow-up: 21 (43%) had primary and 27 (55%) had secondary low testosterone. Survivors of testicular cancer with higher body mass index were more likely to display low testosterone, both primary (p = 0.032) and secondary (p = 0.028). Our data did not show evidence of an association between older age or chemotherapy use and low testosterone in our cohort. CONCLUSIONS: Low total serum testosterone was common in survivors of testicular cancer, and associated with a higher body mass index prior to orchidectomy, suggesting that elevated body mass index may contribute to low testosterone in this population, and that body weight, diet, and exercise should be addressed in testicular cancer follow-up.

RéSUMé: CONTEXTE: L'hypogonadisme primaire est une complication reconnue chez les survivants d'un cancer du testicule. Cependant, l'hypogonadisme secondaire peut résulter d'autres causes qui suppriment l'axe hypothalamo-hypophysaire, notamment l'obésité, les glucocorticoïdes à forte dose, la défaillance chronique des organes cibles et le diabète. Le but de cette étude était d'explorer un faible taux de testostérone totale sérique chez les survivants australiens d'un cancer du testicule, et d'examiner les associations avec l'indice de masse corporelle, l'âge et l'utilisation antérieure d'une chimiothérapie. Les données cliniques, y compris la taille, le poids, le diagnostic, le traitement et les évaluations hormonales au cours du suivi, ont été extraites de l'étude Chemocog de l'Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group (2007­2012), accompagnées de données, provenant de deux centres australiens à fort volume de prise en charge de cancers du testicule, incluses dans le registre du cancer du testicule iTestis (2012­2019). Un taux faible de testostérone a été défini par une concentration sérique de testostérone (T) < 10 nmol/L, et a été classé comme primaire pour une concentration sérique d'hormone lutéinisante (LH) > 8 UI/L, sinon comme secondaire. RéSULTATS: Deux cent quatre-vingt-cinq personnes atteintes d'un cancer des testicules de stade 1 ou avancé ont été incluses. Parmi ceux-ci, 105 (37%) ont été traités par orchidectomie et chimiothérapie. Quarante-neuf (17%) répondaient aux critères d'un taux faible de testostérone au cours du suivi: 21 (43%) avaient un taux faible de testostérone primaire et 27 (55%) un faible taux secondaire. Les survivants d'un cancer du testicule avec un indice de masse corporelle plus élevé étaient plus susceptibles de présenter un taux faible de testostérone, à la fois primaire (p = 0,032) et secondaire (p = 0,028). Nos données n'ont pas montré de preuve d'une association entre un âge avancé ou l'utilisation de la chimiothérapie, et un taux faible de testostérone, dans notre cohorte. CONCLUSIONS: Un faible taux de testostérone sérique totale était fréquent chez les survivants d'un cancer du testicule, et associé à un indice de masse corporelle plus élevé avant l'orchidectomie; ceci suggère qu'un indice de masse corporelle élevé peut contribuer à un faible taux de testostérone dans cette population, et que le poids corporel, l'alimentation et l'exercice devraient être pris en compte dans le suivi du cancer du testicule.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3ß-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial.

PURPOSE: The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components. PATIENTS AND METHODS: Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A). RESULTS: We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD. CONCLUSION: THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.

Health-related quality of life with comprehensive geriatric assessment guided care versus usual care in older adults with cancer: A systematic review and meta-analysis of randomized trials.

BACKGROUND: To evaluate if comprehensive geriatric assessment (CGA)-guided care improves health-related quality of life (HRQL) in older adults with cancer compared to usual care. METHODS: Relevant randomized controlled trials (RCTs) were identified through biomedical databases. Meta-analyses using DerSimonian-Laird model summarized the difference in the mean change of HRQL scores from baseline across various time points, with evidence certainty assessed by the GRADE tool. Logistic regression via generalized estimating equations analyzed predictors of HRQL improvement. RESULTS: Potential improvement in the global HRQL score by CGA-guided care at 3 months (Cohen's d 0.27, 95 % CI -0.03-0.58, moderate certainty), could not be excluded. Larger RCTs or those mandating CGA before initiating anti-cancer treatment were predictors of improved HRQL. CONCLUSION: The effects of CGA-guided care on HRQL were variable. Larger RCTs and those mandating pre-treatment CGA tended to report improved HRQL.

Estimating survival scenarios in advanced or metastatic gastric and oesophageal adenocarcinoma: a systematic review of randomized-controlled trials.

BACKGROUND: We aimed to summarize survival data from RCTs in patients with GO adenocarcinoma; estimate and explain worst-, typical-, and best-case-scenarios of survival time; and determine if simple multiples of median overall survival (mOS) could estimate these percentiles. METHODS: We systematically searched RCTs of systemic therapies for GO adenocarcinoma published 2000-2022. The following key percentiles were extracted from overall survival curves: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We tested if these percentiles could be estimated by simple multiples of mOS: 0.25 of the median for the 90th percentile, 0.5 for the 75th, 2 for the 25th, and 3 for the 10th. RESULTS: We identified 44 trials (22,447 participants). For first line chemotherapy and immunotherapy combined (CI) trials (n = 3) worst-to-best case survival time ranged from 4 months to not reached, compared to 3-30 months for other trials (n = 27) and 1-23 months for subsequent lines (n = 14). Simple multiples of mOS accurately estimated the following survival percentiles: 90th (n = 3/3 trials), 75th (n = 3/3), and 25th (n = 2/3) in first line CI trials. In other first line trials, the mOS accurately estimated the 90th survival percentile in n = 22/27 trials, 75th percentile in n = 26/27, 25th percentile in 27/27 trials, and 10th percentile in 22/27 trials. Simple multiples of the mOS accurately predicted the 90th, 75th, 25th, and 10th survival percentiles in the majority of trials of second and subsequent lines apart from chemotherapy and immunotherapy only trials. CONCLUSION: We provide realistic, evidence-based prognostic information as scenarios for survival time which can inform clinical decision-making. Simple multiples of the mOS accurately estimated the percentiles for most groups.

Challenges of estimating treatment effects after a positive interim analysis.

BACKGROUND: This research investigates why a beneficial treatment effect reported at the first interim analysis (IA) may diminish at a subsequent analysis (SA). We examined three challenges in interpreting treatment effects from randomized clinical trials (RCTs) after the first positive IA: overestimation bias; non-proportional hazards; and heterogeneity in recruitment. We investigate how a penalized estimation method can address overestimation bias, and discuss additional factors to consider when interpreting positive IA results. METHODS: We identified oncology RCTs reporting positive results at the initial IA and a SA for event-free (EFS) and overall survival (OS). We modeled: (1) the hazard ratio at IA (HRIA) versus its timing as measured by the information fraction (IF; i.e., events at IA versus total events sought); and (2), the ratio of HRIA to HRSA (rHR) versus the IF. This was repeated for HRIA adjusted for overestimation bias. Examples of the other two challenges were sought. RESULTS: Amongst 71 RCTs, HRIA were positively associated with the IF (slope: EFS 0.83, 95 % CI 0.44-1.22; OS 0.25, 95 % CI 0.10-0.41). HRIA tended to exaggerate HRSA, and more so the lower the IF (slope rHR versus IF: EFS 0.10, 95 % CI - 0.22 to 0.42; OS 0.26, 95 % CI 0.07-0.46). Adjusted HRIA did not exaggerate HRSA (slope rHR versus IF: EFS - 0.14, 95 % CI - 0.67 to 0.39; OS 0.02, 95 % CI - 0.26 to 0.30). Examples of two other challenges are shown. CONCLUSION: Overestimation bias, non-proportional hazards, and heterogeneity in recruitment and other important treatments should be considered when communicating estimates of treatment effects from positive IAs.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Validation of Prognostic and Predictive Models for Therapeutic Response in Patients Treated with [177Lu]Lu-PSMA-617 Versus Cabazitaxel for Metastatic Castration-resistant Prostate Cancer (TheraP): A Post Hoc Analysis from a Randomised, Open-label, Phase 2 Trial.

BACKGROUND: Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [177Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [177Lu]Lu-PSMA compared with standard chemotherapy has not been established. OBJECTIVE: To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective). DESIGN, SETTING, AND PARTICIPANTS: All 200 patients were randomised in the TheraP trial to receive [177Lu]Lu-PSMA-617 (n = 99) or cabazitaxel (n = 101) between February 2018 and September 2019. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [177Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis. RESULTS AND LIMITATIONS: The probability of PSA50 in patients classified as having a favourable outcome was greater in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69-30.80] vs 0.96 [95% CI 0.32-3.05]; p = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [177Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: p = 0.36 and p = 0.41, respectively). CONCLUSIONS: A previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [177Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [177Lu]Lu-PSMA-617 and cabazitaxel. PATIENT SUMMARY: In this report, we validated previously developed statistical models that can predict a response to Lu-PSMA radioligand therapy in patients with advanced prostate cancer. We found that the statistical models can predict patient survival, and aid in determining whether Lu-PSMA therapy or cabazitaxel yields a higher probability to achieve a serum prostate-specific antigen response.