Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes ...of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m
for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio HR, 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.
The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription ...factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.
We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.
A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.
Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).
Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).
To determine if stereotactic ablative ...radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer.
The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.
Patients were randomized in a 2:1 ratio to receive SABR or observation.
The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease.
In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03).
Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.
ClinicalTrials.gov Identifier: NCT02680587.
Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is ...unclear whether patients with low-volume (LV) disease benefit from early D.
To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment PRLT).
Data were accessed from two independent phase III trials of ADT alone or ADT+D—GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.
The primary end point was OS.
Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval CI) 0.68 (95% CI 0.56; 0.82, p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached NR and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials.
There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients.
Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.
The aggregate data of two phase 3 trials show that patients with a high volume of metastatic castrate naive prostate cancer have poorer overall survival (OS) and benefit from androgen deprivation therapy (ADT)+docetaxel. Low-volume patients have longer OS with ADT alone and no clear benefit with adding docetaxel.
Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The ...effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
Trial Registration
ClinicalTrials.gov identifier: NCT00465595
To validate currently used recurrence prediction models for renal cell carcinoma (RCC) by using prospective data from the ASSURE (ECOG-ACRIN E2805; Adjuvant Sorafenib or Sunitinib for Unfavorable ...Renal Carcinoma) adjuvant trial.
Eight RCC recurrence models (University of California at Los Angeles Integrated Staging System UISS; Stage, Size, Grade, and Necrosis SSIGN; Leibovich; Kattan; Memorial Sloan Kettering Cancer Center MSKCC; Yaycioglu; Karakiewicz; and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models along with the TNM staging system were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1Mo) from the ASSURE cohort. The predictive performance of the model was quantified by assessing its discriminatory and calibration abilities.
Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688; 95% CI, 0.686 to 0.689), and the UISS model performed worst (0.556; 95% CI, 0.555 to 0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis.
In RCC, as in many other solid malignancies, clinicians rely on retrospective prediction tools to guide patient care and clinical trial selection and largely overestimate their predictive abilities. We used prospective collected adjuvant trial data to validate existing RCC prediction models and demonstrate a sharp decrease in the predictive ability of all models compared with their previous retrospective validations. Accordingly, we recommend prospective validation of any predictive model before implementing it into clinical practice and clinical trial design.
In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell ...carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.
In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.
Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months IQR 13·4–36·3), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached 95% CI 35·6–not estimable vs 26·6 months 22·1–33·4; hazard ratio HR 0·66 95% CI 0·54–0·80, p<0·0001), progression-free survival (median 8·2 months 95% CI 6·9–10·0 vs 8·3 months 7·0–8·8; HR 0·77 95% CI 0·65–0·90, p=0·0014), and the proportion of patients achieving an objective response (178 42% of 425 vs 124 29% of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached 95% CI not estimable vs 37·9 months 32·2–not estimable; HR 0·71 95% CI 0·59–0·86, p=0·0003), progression-free survival (median 9·7 months 95% CI 8·1–11·1 vs 9·7 months 8·3–11·1; HR 0·85 95% CI 0·73–0·98, p=0·027), and the proportion of patients achieving an objective response (227 41% of 550 vs 186 34% of 546 p=0·015). In all treated patients, the most common grade 3–4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 10% of 547), increased amylase (31 6%), and increased alanine aminotransferase (28 5%), whereas in the sunitinib group they were hypertension (90 17% of 535), fatigue (51 10%), and palmar-plantar erythrodysaesthesia (49 9%). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.
The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.
Bristol-Myers Squibb and ONO Pharmaceutical.
Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and ...enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators ...experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
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