PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes for Patients with High- or Low-volume Metastatic Hormone-sensitive Prostate Cancer: Analyses of the Randomized Phase 3 ARASENS Study.

BACKGROUND AND OBJECTIVE: Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes. METHODS: ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses. KEY FINDINGS AND LIMITATIONS: The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21-0.31) in the overall population, 0.30 (95% CI 0.24-0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047-0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37-0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes. PATIENT SUMMARY: For patients with metastatic hormone-sensitive prostate cancer being treated with androgen deprivation therapy and docetaxel, PSA (prostate-specific antigen) became undetectable (below 0.2 ng/ml) in 67% of those also receiving darolutamide versus 29% of patients also receiving placebo. On average, patients achieving undetectable PSA lived longer than patients with detectable PSA.

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide.

BACKGROUND: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. OBJECTIVE: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. DESIGN, SETTING, AND PARTICIPANTS: PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. RESULTS AND LIMITATIONS: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. CONCLUSIONS: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. PATIENT SUMMARY: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

Race and Treatment Outcomes in Patients With Metastatic Castration-Sensitive Prostate Cancer: A Secondary Analysis of the SWOG 1216 Phase 3 Trial.

Importance: Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. Race and social determinants of health influence prostate cancer-specific mortality and overall survival (OS); however, in a previous trial, Black patients did not have inferior outcomes compared with White patients, possibly because of equitable access to care available in a clinical trial setting. Objective: To compare differences in survival outcomes of patients with metastatic castration-sensitive prostate cancer (mCSPC) by race in a phase 3 trial with a large proportion of Black patients. Design, Setting, and Participants: This secondary analysis of patient-level data of a prospective phase 3 randomized clinical trial included patients with newly diagnosed mCSPC enrolled between March 1, 2013, and July 15, 2017. Analysis was conducted between December 2022 and February 2023. Interventions: Patients receiving androgen deprivation therapy were randomized (1:1) to receive either orteronel 300 mg orally twice daily (experimental group) or bicalutamide 50 mg orally daily (control group). Main Outcomes and Measures: OS, with progression-free survival (PFS) as a secondary end point. Results: Among 1313 participants, 135 (10%) identified as Black and 1077 (82%) as White, with an equal racial distribution between groups. Black patients were younger (median [IQR] age, 65.8 [60-70] vs 68.4 [62.5-74.1] years; P = .001) and had a higher median (IQR) baseline prostate-specific antigen response rate than White patients (54.7 [19.8-222.0] vs 26.7 [9.2-96.0] ng/mL; P < .001). At a median follow-up of 4.9 years, Black and White patients had similar median PFS (2.3 years; 95% CI, 1.8-1.4 years vs 2.9 years; 95% CI, 2.5-3.3 years; P = .71) and OS (5.5 years; 95% CI, 4.8-NR vs 6.3 years; 95% CI, 5.7-NR; P = .65). The multivariable analysis confirmed similar PFS and OS after adjusting for known prognostic factors. No interaction between race and treatment was observed. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial studying androgen deprivation therapy with first- or second-generation androgen receptor pathway inhibitors, both Black and White patients demonstrated similar OS and PFS. Equitable access to care may reduce historical differences in outcomes between Black and White patients with advanced prostate cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT01809691.

Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346).

PURPOSE: Frequent prostate specific antigen testing for screening and monitoring prostate cancer has led to significant stage migration. We evaluated whether overall survival in hormone naïve patients with metastatic prostate cancer has improved during the era of prostate specific antigen use. We also assessed whether any patient subsets benefited differentially during this period. MATERIALS AND METHODS: We compared overall survival in 3 sequential phase III trials of 3,096 men with hormone naïve, metastatic prostate cancer who received similar androgen deprivation therapy, including 2 trials performed before the prostate specific antigen era (S8494 and S8894) and the other done during this era (S9346). Overall survival was adjusted for patient and disease risk factors in the latter 2 trials. Subgroups were evaluated by interactions of risk factors with trial. RESULTS: Median overall survival was 30 months in S8494, 33 months in S8894 and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 than in S8894 (HR 0.78, 95% CI 0.70, 0.87, p <0.001). The improvement in overall survival was greater in black American men (test of interaction p = 0.008). In S8494 and S8894 median survival for black men was 27 months, and 34 and 35 months for nonblack men, respectively. This racial difference disappeared in S9346 with overall survival of 48 and 49 months in black and nonblack men, respectively. CONCLUSIONS: Adjusting for risk factors, overall survival was significantly improved in the post-prostate specific antigen era trial. However, it cannot be concluded that this was attributable only to prostate specific antigen monitoring. Black men now have overall survival comparable to that of white men. Current estimates of survival should be used to design new trials in this population.

Orteronel for Metastatic Hormone-Sensitive Prostate Cancer: A Multicenter, Randomized, Open-Label Phase III Trial (SWOG-1216).

PURPOSE: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS: In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS: Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months (P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION: The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.

Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2-ERG fusions.

BACKGROUND: Men with early-onset prostate cancer are at increased risk for cancer-related mortality, yet the prevalence and spectrum of molecular alterations in this patient population is unknown. Here, we analyze comprehensive genomic profiling data to characterize the molecular drivers of early-onset prostate cancer in patients with clinically advanced and metastatic disease. METHODS: Next-generation sequencing was ordered as a part of routine clinical care for 10,189 patients with prostate cancer between 02/2013 and 03/2020 using commercially available comprehensive genomic profiling. RESULTS: Deidentified genomic data for 10,189 unique patients with prostate cancer were obtained (median age = 66 y, range = 34-90 y). 439 patients were ≤50 y (4.3%), 1928 patients were between ages of 51 and 59 y (18.9%), and 7822 patients were ≥60 y  (76.8%). Of metastatic biopsy sites, lymph node, liver, and bone were the most common in all groups, accounting for 60.2% of all specimens. Overall, 97.4% of patients harbored pathologic genomic alterations. The most commonly altered genes were TP53, TMPRSS2-ERG, PTEN, AR, MYC, MLL2, RAD21, BRCA2, APC, SPOP, PIK3CA, RB1, MLL3, CDK12, ATM, and CTNNB1. Patients ≤50 y harbored significantly more TMPRSS2-ERG fusions than patients ≥60 y, while AR copy number alterations as well as SPOP and ASXL1 mutations were significantly less frequent. CONCLUSIONS: Clinically advanced and metastatic early-onset prostate cancer is a distinct clinical subgroup with characteristic genomic alterations including increased frequency of TMPRSS2-ERG fusions and fewer AR, SPOP, and ASXL1 alterations.

Baseline Circulating Tumor Cell Count as a Prognostic Marker of PSA Response and Disease Progression in Metastatic Castrate-Sensitive Prostate Cancer (SWOG S1216).

PURPOSE: In metastatic castrate-sensitive prostate cancer (mCSPC), combined androgen axis inhibition is a standard of care. Noninvasive biomarkers that guide initial therapy decisions are needed. We hypothesized that CellSearch circulating tumor cell (CTC) count, an FDA-cleared assay in metastatic castrate-resistant prostate cancer (mCRPC), is a relevant biomarker in mCSPC. EXPERIMENTAL DESIGN: SWOG S1216 is a phase III prospective randomized trial of androgen deprivation therapy (ADT) combined with orteronel or bicalutamide for mCSPC. CellSearch CTC count was measured at registration (baseline). Prespecified CTC cut-off points of 0, 1-4, and ≥5 were correlated with baseline patient characteristics and, in a stratified subsample, were also correlated with two prespecified trial secondary endpoints: 7-month PSA ≤0.2 ng/mL versus 0.2-4.0 versus >4.0 (intermediate endpoint for overall survival); and progression-free survival (PFS) ≤ versus >2 years. RESULTS: A total of 523 patients submitted baseline samples, and CTCs were detected (median 3) in 33%. Adjusting for two trial stratification factors (disease burden and timing of ADT initiation), men with undetectable CTCs had nearly nine times the odds of attaining 7-month PSA ≤ 0.2 versus > 4.0 [OR 8.8, 95% confidence interval (CI), 2.7-28.6, P < 0.001, N = 264] and four times the odds of achieving > 2 years PFS (OR 4.0, 95% CI, 1.9-8.5, P < 0.001, N = 336) compared with men with baseline CTCs ≥5. CONCLUSIONS: Baseline CTC count in mCSPC is highly prognostic of 7-month PSA and 2-year PFS after adjusting for disease burden and discriminates men who are likely to experience poor survival outcomes.

A sequential treatment approach to myoinvasive urothelial cancer: a phase II Southwest Oncology Group trial (S0219).

PURPOSE: We conducted a phase II trial of neoadjuvant paclitaxel, carboplatin and gemcitabine as well as transurethral resection of bladder tumor to evaluate the clinical T0 (cT0) rate with paclitaxel, carboplatin and gemcitabine, and to study cystoscopic surveillance or immediate cystectomy for patients with cT0 status following chemotherapy. MATERIALS AND METHODS: Patients with T2-T4a chemotherapy and radiation naive urothelial cancer were eligible. T2+ tumor had to be diagnosed by transurethral bladder tumor resection followed by a second transurethral bladder tumor resection to confirm persistent disease within 16 weeks of the first resection. Three cycles of paclitaxel, carboplatin and gemcitabine were administered within 8 weeks of the second transurethral bladder tumor resection. Patients with cT0 status after paclitaxel, carboplatin and gemcitabine therapy could elect immediate cystectomy or cystoscopic surveillance, and those with greater than cT0 status were to undergo immediate cystectomy. RESULTS: Of 77 patients 74 were assessable, and cT0 status after paclitaxel, carboplatin and gemcitabine was achieved in 34 of 74 patients (46%). Of the 34 patients with cT0 status 10 underwent immediate cystectomy, 6 of whom had persistent cancer. Persistent tumor at transurethral bladder tumor resection was seen in 28 patients (38%) and 21 underwent cystectomy. Thus, 35 of 74 patients underwent cystectomy. With a median followup of 22 months 2-year overall survival was 59% (95% CI 45, 72) and among cT0 cases it was 75% (95% CI 57, 93). CONCLUSIONS: Although neoadjuvant paclitaxel, carboplatin and gemcitabine had a promising 46% cT0 rate, the study failed to meet the primary objective as there was an unacceptably high rate (60%) of persistent cancer at cystectomy in patients presumed to have pT0 status. Patients completing neoadjuvant chemotherapy should strongly consider definitive local therapy rather than cystoscopic surveillance regardless of post-chemotherapy cT0 status.

Inflammatory Bowel Disease and the Risk of Prostate Cancer.

BACKGROUND: There are limited data examining the risk of prostate cancer (PCa) in patients with inflammatory bowel disease (IBD). OBJECTIVE: To compare the incidence of PCa between men with and those without IBD. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, matched-cohort study involving a single academic medical center and conducted from 1996 to 2017. Male patients with IBD (cases=1033) were randomly matched 1:9 by age and race to men without IBD (controls=9306). All patients had undergone at least one prostate-specific antigen (PSA) screening test. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier and multivariable Cox proportional hazard models, stratified by age and race, evaluated the relationship between IBD and the incidence of any PCa and clinically significant PCa (Gleason grade group ≥2). A mixed-effect regression model assessed the association of IBD with PSA level. RESULTS AND LIMITATIONS: PCa incidence at 10yr was 4.4% among men with IBD and 0.65% among controls (hazard ratio [HR] 4.84 [3.34-7.02] [3.19-6.69], p<0.001). Clinically significant PCa incidence at 10yr was 2.4% for men with IBD and 0.42% for controls (HR 4.04 [2.52-6.48], p<0.001). After approximately age 60, PSA values were higher among patients with IBD (fixed-effect interaction of age and patient group: p=0.004). Results are limited by the retrospective nature of the analysis and lack of external validity. CONCLUSIONS: Men with IBD had higher rates of clinically significant PCa when compared with age- and race-matched controls. PATIENT SUMMARY: This study of over 10000 men treated at a large medical center suggests that men with inflammatory bowel disease may be at a higher risk of prostate cancer than the general population.

Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426).

BACKGROUND: Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi-institutional prospective trial. METHODS: Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate-specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration. RESULTS: A total of 210 eligible and evaluable patients had a median follow-up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of >or=50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression-free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12-month or greater progression-free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA-only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response. CONCLUSIONS: These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (>or=1 year) in approximately 19% of patients.

Southwest Oncology Group phase II study of ispinesib in androgen-independent prostate cancer previously treated with taxanes.

PURPOSE: The mitotic spindle has proven to be an effective therapeutic target in antineoplastic efforts. In this study, we sought to assess the efficacy of ispinesib, a mitotic kinesin spindle protein (KSP) inhibitor in androgen-independent prostate cancer progressing after docetaxel. PATIENTS AND METHODS: Patients were treated with ispinesib 18 mg/m2 every 21 days and assessed for prostate-specific antigen (PSA) and measurable disease response at regular intervals. Kinesin spindle protein expression in archival tumors, population ispinesib pharmacokinetics, and pharmacodynamic assessments of circulating lymphocytes were included. RESULTS: The study was terminated after first stage because no responses were seen in the first 21 patients. Median duration of PSA or clinical progression-free survival was 9 weeks. Plasma concentrations of ispinesib were comparable with those observed in previous phase I investigations. Immunohistochemical analysis of archival tumor specimens did not demonstrate significant KSP expression in most of the prostate cancer cases studied. Pharmacodynamic assessments of circulating lymphocytes from patients receiving ispinesib showed an absence of monopolar spindle formation, as would be expected if the drug were having its expected effects. CONCLUSION: Ispinesib was inactive in this study of patients with androgen-independent, and largely docetaxelresistant, prostate cancer. The lack of efficacy might be explained by the low expression of the drug target seen in prostate cancer, whereas not detecting monopolar spindles in circulating lymphocytes with drug treatment likely reflects the lack of dividing cells in peripheral blood.

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.

BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer. METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

Abiraterone Acetate for Metastatic Prostate Cancer in Patients With Suboptimal Biochemical Response to Hormone Induction.

IMPORTANCE: Men with metastatic prostate cancer who have a poor response to initial androgen-deprivation therapy (ADT), as reflected by a prostate-specific antigen (PSA) level higher than 4.0 ng/mL after 7 months of ADT, have a poor prognosis, based on historical controls. OBJECTIVE: To determine the efficacy of abiraterone acetate with prednisone in these high-risk patients with a suboptimal response to hormonal induction. DESIGN, SETTING, AND PARTICIPANTS: A phase 2 single-arm study was conducted through the National Clinical Trials Network-Southwest Oncology Group. Eligible patients had metastatic prostate cancer and a PSA level higher than 4.0 ng/mL between 6 and 12 months after starting ADT. The PSA level could be rising or falling at the time of enrollment, but had to be higher than 4.0 ng/mL. No previous chemotherapy or secondary hormonal therapies were allowed, except in patients receiving a standard, first-generation antiandrogen agent with a falling PSA level at the time of enrollment; this therapy was continued in this cohort. Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily was administered to all participants. A total of 41 men were enrolled between the trial's activation on August 9, 2011, and closure on August 1, 2013. Data analysis was conducted from March 21 to November 29, 2016. INTERVENTIONS: Abiraterone acetate, 1000 mg, once daily by mouth with prednisone, 5 mg, by mouth twice daily. MAIN OUTCOMES AND MEASURES: The primary end point was a PSA level of 0.2 ng/mL or lower within 12 months of starting abiraterone acetate plus prednisone. A partial response (PR) was a secondary end point, defined as a PSA level reduction to lower than 4.0 ng/mL but higher than 0.2 ng/mL. RESULTS: Of the 41 men enrolled, 1 did not receive any protocol treatment and was excluded from analysis. The median (range) age of the 40 participants was 66 (39-85) years. Five (13%) patients achieved a PSA level of 0.2 ng/mL or lower (95% CI, 4%-27%). Thirteen (33%) additional patients achieved a partial response, with a reduction in the PSA level to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Sixteen (40%) patients had no PSA response and 6 (15%) were not assessable and assumed to be nonresponders. The median progression-free survival was 17.5 months (95% CI, 8.6-25.0 months) and the median overall survival was 25.8 months (95% CI, 15.7-25.8 months). There was 1 incident each of grade 4 adverse events of alanine aminotransferase level elevation and rectal hemorrhage. Eleven patients reported grade 3 adverse events. CONCLUSIONS AND RELEVANCE: This study did not reach its prescribed level of 6 PSA responses of 0.2 ng/mL or lower, although 5 responses were observed. The overall survival and progression-free survival rates observed in this trial are encouraging compared with historical controls. The therapy was generally well tolerated, without any clear signal of any unexpected adverse effects.

Validation of the Association of RECIST Changes With Survival in Men With Metastatic Castration-Resistant Prostate Cancer Treated on SWOG Study S0421.

BACKGROUND: Phase 2 trials evaluating new agents for metastatic castration-resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel. PATIENTS AND METHODS: Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors. RESULTS: Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different (P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5-8.8), 13.4 (11.4-15.6), and 16.3 (10.0-19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42-4.29) compared to patients with an uPR (P = .002). CONCLUSION: The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate-specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials.

Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group.

PURPOSE: To determine the response rate, survival and toxicity of infusional cisplatin plus fluorouracil (CF) versus cisplatin plus paclitaxel (CP) in patients with incurable squamous cell cancer of the head and neck, with the hypothesis that CP is superior. PATIENTS AND METHODS: Two hundred eighteen patients with locally advanced, recurrent, or metastatic disease were randomly assigned to CF (cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4) or CP (cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1). Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease. The primary outcome was overall survival. Secondary outcomes included response rate and toxicity. RESULTS: No significant difference in overall survival or response rate was seen. Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group. Objective response rate (complete response plus partial response) was 27% in the CF group and 26% in the CP group. Toxicity was similar between groups, with the most frequent including myelosuppression, thrombocytopenia, anemia, nausea, vomiting, and stomatitis. A total of 12 deaths occurred (CF, seven; CP, five) during treatment; eight from infection, two from hemorrhage, one from cardiac causes and one from unknown causes. Gastrointestinal and hematologic toxicities were more common in the CF group, whereas neurotoxicity was equivalent between groups. CONCLUSION: This phase III, randomized, multicenter trial showed no difference in survival between patients treated with CF or CP.

Phase II evaluation of early oral estramustine, oral etoposide, and intravenous paclitaxel combined with hormonal therapy in patients with high-risk metastatic prostate adenocarcinoma: Southwest Oncology Group S0032.

OBJECTIVES: To assess the efficacy of a multiagent taxane-based chemotherapy combined with hormonal therapy in men with metastatic androgen-dependent prostate cancer in a multicenter, cooperative group, single-arm trial. METHODS: A total of 41 patients with newly diagnosed metastatic prostate cancer involving both the axial and the appendicular skeletons or viscera were enrolled. Of the 41 patients, 35 were treated with combined androgen blockade and ≤4 cycles of oral estramustine (280 mg orally 3 times daily) and etoposide (50 mg/m(2) daily) for 14 days of each 21-day cycle, with paclitaxel (135 mg/m(2) intravenously within 1 hour) on day 2 of each cycle. Chemotherapy was started within 30 days of the initiation of hormonal therapy. The patients were followed up to determine the progression-free survival. RESULTS: The 35 patients received a total of 126 cycles of chemotherapy, with 30 receiving all 4 cycles. The median progression-free survival for the evaluable population was 13 months (95% confidence interval 10-16), with a median overall survival of 38 months (95% confidence interval 28-49). The main toxicities were myelosuppression, with 9 patients experiencing grade 3 or greater neutropenia and 1 developing grade 4 thrombocytopenia. One patient died of neutropenic infection. Thrombosis embolism occurred 4 times (3 of grade 4 and 1 of grade 3), with 1 episode of grade 4 cardiac ischemia. CONCLUSIONS: The results of our study have shown that the administration of chemotherapy to this population is feasible, with moderate toxicity. Taxane-based chemotherapy did not demonstrate significant efficacy in this high-risk population of patients with a poor prognosis.

Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study.

PURPOSE: Men with high-risk features (extraprostatic extension or high Gleason grade) face a high risk of prostate cancer recurrence after radical prostatectomy. Clinical trials of adjuvant systemic therapy for such patients have been limited. PATIENTS AND METHODS: The SWOG (Southwest Oncology Group) S9921 study randomly assigned 983 men with high-risk features at prostatectomy to receive adjuvant therapy with androgen deprivation (ADT) alone or in combination with mitoxantrone chemotherapy. ADT consisted of goserelin and bicalutamide for 2 years. RESULTS: Although the final primary treatment comparison results are not ready for publication, this article reports results in the ADT-alone control arm with a median follow-up of 4.4 years. For these 481 men, the estimated 5-year biochemical failure-free survival is 92.5% (95% CI, 90 to 95), and 5-year overall survival is 95.9% (95% CI, 93.9 to 97.9). CONCLUSION: The results of this trial, taken in context, make a compelling argument for counseling all high-risk patients with prostate cancer about adjuvant ADT. This article discusses the challenges in the design and implementation of clinical trials to take the next step forward in adjuvant therapy for prostate cancer because of the excellent survival achieved with currently available therapies and highlights the need for better molecular markers to personalize care.

Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer.

PURPOSE: Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castration-resistant prostate cancer. EXPERIMENTAL DESIGN: Eligible men had castration-resistant prostate cancer treated with one prior chemotherapy. Subjects were treated with 6 mg/kg CNTO328 i.v. every 2 weeks for 12 cycles. Response was assessed after every three cycles. Primary end point was prostate-specific antigen (PSA) response rate defined as a 50% reduction. Accrual was planned in two stages, with 20 eligible patients in the first stage and 40 overall. Plasma cytokines and growth factors were measured by Luminex. RESULTS: Fifty-three eligible subjects had all received prior taxane therapy. Two (3.8%; 95% CI, 0.5-13.0%) had PSA response. None of the 31 patients with measurable disease had a RECIST (Response Evaluation Criteria in Solid Tumors) response but 7 (23%) had stable disease. With median follow-up of 14.8 months, median progression-free survival was 1.6 months (95% CI, 1.6-1.7) and median overall survival was 11.6 months (95% CI, 7.5-19.0). Grade 3/4 toxicities included disseminated intravascular coagulation (1), central nervous system ischemia (1), elevated aspartate aminotransferase (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leukopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (interquartile range, 2.5-41.5). Patients with IL-6 >12.5 pg/mL had worse survival than those with levels <12.5 pg/mL (53% versus 94%; P = 0.02). After treatment, IL-6 levels were >250-fold higher. Thirty-two of 38 patients had a decline in C-reactive protein plasma levels at 6 weeks. CONCLUSIONS: CNTO328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Declining C-reactive protein levels during treatment may reflect biological activity. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis.