Trial Of Androgen Deprivation Therapy Research Articles

1646P A multicohort phase II trial of androgen deprivation therapy (ADT), docetaxel (DOCE) and nivolumab (NIVO) in patients (pts) with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) enriched for inflamed tumours and DNA damage repair (DDR) alterations: Cohort 3 results

1646P A multicohort phase II trial of androgen deprivation therapy (ADT), docetaxel (DOCE) and nivolumab (NIVO) in patients (pts) with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) enriched for inflamed tumours and DNA damage repair (DDR) alterations: Cohort 3 results

Primary analysis of STARTAR: A phase 2 salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

5016 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. For high risk PSA recurrence, current standard ADT duration is up to 2 years with RT; shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo enzalutamide with ADT/RT had 3-year progression free survival (PFS) of 53% in a high risk population, including lymph node (LN) positive. Given docetaxel (doce) improves survival in mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide (apa) and doce in this setting. Methods: STARTAR is a multicenter investigator initiated phase 2 trial for salvage treatment of PSA recurrent PC post-RP, conducted in the DOD Prostate Cancer Clinical Trials Consortium. Key inclusion criteria included Gleason 7 with T3/positive margin/N1 or Gleason 8-10 PC, PSA relapse <4 years post-RP (inclusion PSA 0.2-4 ng/mL), and <4 positive LNs, standard imaging negative. Patients (pts) received ADT with apa for 9 months, RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 wks) starting wk 8, and then completed 6 cycles of concurrent doce 75mg/m2 q3 wks. The primary endpoint was 36 month PFS, defined as composite of freedom from PSA>0.2 + post-RT nadir with subsequent rise, clinical progression, other therapy start, or death, among pts with testosterone (T) recovery (>100ng/dL). Kaplan-Meier estimates for PFS were used to determine landmark 24 mo and 36 mo rates and compared to PFS rates from prior trials using a binomial test. Results: From 3/2018 to 2/2020, 39 pts were enrolled. As of 12/2022 data cutoff, median follow up was 36 months. Baseline characteristics: Gleason 7 in 54%; Gleason 8-10 in 46%; 23% LN positive; median PSA 0.58 ng/mL (range 0.21-3.40), and median time from RP 7.6 mo (range 2-98). 37 pts (95%) and 23 pts (62%) completed at least 1 and all 6 cycles doce, respectively. All pts achieved undetectable PSA nadirs. At 24mo and 36mo, PFS rates were 84% and 72%, respectively, with 95% pts recovering T at 36 mo. Compared to 40% historical PFS and 53% STREAM PFS rates, the 72% 36-mo PFS rate was statistically significantly improved (p<0.001 and p=0.013, respectively). Common any-grade adverse events (AEs) included 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with 5% febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apa, salvage RT, and 6 cycles of doce for high risk PSA recurrence, the primary endpoint 3-year PFS rate improved to 72%, indicating durable remissions beyond historic controls. Intensifying systemic treatments in the non-metastatic hormone sensitive but high risk salvage setting may be feasible and efficacious, with fewer pts experiencing cancer progression over time. Clinical trial information: NCT03311555 .

APPROACH trial: Multimodal approach in patients with mHSPC: A pragmatic, randomized, phase 3 trial of androgen-deprivation therapy (ADT) plus apalutamide (APA) versus ADT plus apalutamide (APA) and local treatment—Meet-URO 29 study.

TPS5115 Background: it is reasonable to offer radiotherapy (RT) to improve outcomes for patients with newly diagnosed M1 prostate cancer with < 5 bone metastases (HORRAD) or low volume disease (STAMPEDE) (Burdett, S et al., Eur. Urol. 2019). Data from clinical randomized trials evaluating feasibility and overall benefit of cytoreductive radical prostatectomy (cRP) in oligometastatic ormone sensitive patients are not available. The rationale for performing cytoreductive radical prostatectomy is to eliminate lethal clones ofcastration-resistant intraprostatic PCa, which can favor the process of metastasis (A Heidenreich et al. Current Opinion in Urology 2020), in order to improve OS and PFS and to prevent local progression and correlated events. Methods: APPROACH is an Italian multicenter study, which is enrolling ~566 pts with oligometastatic hormone sensitive prostate cancer who are candidates to receive treatment with apalutamide. After 6 months from the start of treatment, patients will be randomized 1:1 to receive local treatment or not in addition to apalutamide (investigator's choice between primary radiotherapy and cytoreductive prostatectomy). Primary end point: To determine whether treatment with apalutamide plus ADT for 6 months followed by locoregional treatment with radiotherapy or radical prostatectomy has better efficacy than treatment with apalutamide plus ADT alone in terms of radiographic progression-free survival (rPFS). Secondary end points: To evaluate tumor shrinkage after locoregional approach and to evaluate short and long-term side effects after locoregional surgery or RT, time to PSA progression, time to castration resistance, cancer specific survival, overall survival and quality of life according to EPIC-26 and EQ-5D-5L questionnaires. Clinical trial information: NCT05649943 .

Androgen Drives the Expression of SARS-CoV-2 Entry Proteins in Sinonasal Tissue.

Men have higher morbidity and mortality from COVID-19 than women, possibly due to androgen receptor-regulated viral entry protein expression. This led to a clinical trial of androgen deprivation therapy (ADT), which has not shown a significant benefit in the outcomes among hospitalized male COVID-19 patients. The aim of this study was to explore biological explanations for the failure of ADT to mitigate clinical outcomes in men with severe COVID-19 by assessing the role of androgen in regulating viral entry protein expression in the upper and lower respiratory tract. Immunohistochemistry was used to assess the expression of transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) and how it correlated to androgen receptor expression in the sinonasal epithelium, minor salivary glands of the sinus, lacrimal glands, and lungs from mice pretreated with and without castration and ADT as well as the sinonasal epithelium obtained from healthy human donors and hospitalized COVID-19 patients. In murine models, castration and ADT treatment downregulated the expression of TMPRSS2 and ACE2 in the sinonasal epithelium, minor salivary glands of the sinus, and lacrimal glands, but not in the lungs. Correlative analyses using human tissue also showed a potential role of ADT in men during the early sinonasal phase but not in the later lung phase of SARS-CoV-2 infection. Our study suggests a potential benefit of ADT in male patients with early COVID-19 when the virus enters the nasopharynx, but not in those with advanced disease. The downregulation of viral entry proteins in the upper respiratory system following androgen blockade may be a key mechanism for this effect.

Bone Biomarkers and Subsequent Survival in Men with Hormone-sensitive Prostate Cancer: Results from the SWOG S1216 Phase 3 Trial of Androgen Deprivation Therapy with or Without Orteronel

BackgroundBone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC). ObjectiveBone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel. Design, setting, and participantsPatients were randomly divided into training (n = 316) and validation (n = 633) sets. Recursive partitioning and Cox proportional hazard models were employed. Outcome measurements and statistical analysisBone resorption (C-telopeptide and pyridinoline) and bone formation markers (C-terminal collagen propeptide and bone alkaline phosphatase) were assessed from patient sera. Results and limitationsOf 1279 men, 949 had evaluable baseline bone biomarkers. Optimal cutoffs were identified to define elevated levels of each of the four biomarkers (all p < 0.05) that were associated with worse OS. After adjusting for clinical risk factors in the validation set, elevated bone biomarkers were statistically significantly associated with an increased risk of death (hazard ratios ranging from 1.37 to 1.92). Recursive partitioning algorithms applied to the training set identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 yr, respectively) based on combinations of bone biomarkers. These results were confirmed in the validation set. ConclusionsIn men with HSPC initiating androgen deprivation therapy, bone biomarkers are strongly and independently prognostic for OS. Bone biomarker levels alone or in combination with clinical covariates identify unique subsets of men with differential OS outcomes. These results validate the clinical value of bone biomarker assessment in the HSPC state, extending bone biomarker utility beyond the castration-resistant state. Patient summaryIn men with newly diagnosed metastatic prostate cancer, high levels of bone turnover biomarkers are associated with a shorter lifespan.

Phase 3 Randomized Controlled Trial of Androgen Deprivation Therapy with or Without Docetaxel in High-risk Biochemically Recurrent Prostate Cancer After Surgery (TAX3503)

BackgroundNo standard of care exists for patients with high-risk biochemical recurrence (BCR) after prostatectomy. ObjectiveTo evaluate whether addition of docetaxel to androgen deprivation therapy (ADT) improved progression-free survival (PFS) in high-risk BCR patients. Design, setting, and participantsTAX3503 was a multicenter phase 3 trial that randomized patients with high-risk BCR to ADT for 18 mo ± docetaxel (75 mg/m2 q3w for ten cycles). Eligibility included prostate-specific antigen (PSA) ≥1.0 ng/ml after prostatectomy alone or after postoperative radiation therapy, PSA doubling time ≤9 mo, and absence of metastases on computed tomography and bone scintigraphy. Outcome measurements and statistical analysisThe primary endpoint was PFS following testosterone recovery to noncastrate levels (testosterone >50 ng/dl). Secondary endpoints included time to testosterone recovery, overall survival (OS), quality of life, and safety. Results and limitationsBetween September 2007 and May 2011, 413 patients were assigned to ADT ± docetaxel. In 2012, following completion of accrual and treatment, the sponsor withdrew support of the study, and in 2013, a registry was created to secure the primary endpoint. The final analysis included data from the original trial and registry. At a median follow-up of 33.6 mo, 260 patients demonstrated testosterone recovery, which occurred similarly between groups. ADT plus docetaxel trended toward a nonclinically meaningful improvement in PFS (median 26.2 vs 24.7 mo) for the testosterone-recovered population (218 events, hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61–1.04) and in OS for the intention-to-treat population (medians not reached, HR 0.51, 95% CI 0.23–1.10). Grade ≥3 adverse events occurred more frequently in the ADT plus docetaxel group (48.0% vs 10.8%). ConclusionsTAX3503 did not demonstrate a meaningful benefit of adding docetaxel to ADT in patients with high-risk BCR. Testosterone recovery was unaffected by addition of docetaxel to ADT. Patient summaryAddition of docetaxel to androgen deprivation therapy did not meaningfully improve outcomes for men with high-risk biochemically recurrent prostate cancer.

Interim analysis of STARTAR: A phase II salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

90 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. Current standard duration of ADT for high risk PSA recurrence is up to 2 years with RT; therefore shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo of enzalutamide added to ADT/RT had a 3-year progression free survival (PFS) of 53% in high risk patients including lymph node (LN) positive. Given that docetaxel improves survival in men with mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide and docetaxel in this setting. Methods: STARTAR is a multicenter phase 2 trial for salvage treatment of PSA recurrent PC following RP conducted within the US Dept. of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC). Key inclusion criteria included PC with Gleason 7 with T3/positive margin/1-4 positive LNs or Gleason 8-10 disease and PSA relapse within 4 years of RP (min PSA 0.2 ng/mL to max PSA 4 ng/mL). Men with up to 4 positive resected LNs were eligible. Men started ADT with apalutamide, continued with RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 weeks), and finally completed docetaxel 75mg/m2 IV q3 weeks for 6 cycles. Men were treated with ADT and apalutamide for approximately 9 months. The primary endpoint was PSA PFS at 36 months. This interim analysis evaluated secondary endpoints of 1-year PSA recurrence, testosterone recovery, and safety of this treatment sequence. Results: From 3/2018 to 12/2019, 39 men were enrolled at Duke, Wake Forest, Cornell, and the GU Research Network. With a data cutoff in 9/2020, median follow up from enrollment was 14 months. Baseline patient characteristics included Gleason 4+3 = 7 in 54% and Gleason 8-10 in 46%, and 23% LN positive; median PSA at the time of enrollment was 0.58 ng/mL (range 0.21-3.40) and the median time from RP to enrollment was 7 mo (range 2-98). At 1 year, there have been no progression events with 38% (12/31) of men with post-treatment testosterone recovery into normal range (recovery time median 10 mos [1-17 mos]). Common adverse events (AEs) of any-grade at least possibly related to the regimen were 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with neutropenia as the most common grade 3/4 AE (27/39 men, 70%) with two grade 3 febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apalutamide, radiation, and 6 cycles docetaxel in the salvage setting for high risk PSA recurrence, short term outcomes are excellent with no recurrences at 12 months of follow-up. This salvage treatment was well tolerated in the majority of men with the exception of a high rate of drug rashes and neutropenia related to the course of treatment, in line with known safety profiles of the study agents. Clinical trial information: NCT03311555.

Phase I/IIa trial of androgen deprivation therapy, external beam radiotherapy, and stereotactic body radiotherapy boost for high-risk prostate cancer (ADEBAR)

BackgroundTo evaluate the clinical outcomes of combination of androgen deprivation therapy (ADT), whole pelvic radiotherapy (WPRT), and stereotactic body radiotherapy (SBRT) boost in high-risk prostate cancer patients.MethodsThis prospective phase I/IIa study was conducted between 2016 and 2017. Following WPRT of 44 Gy in 20 fractions, patients were randomized to two boost doses, 18 Gy and 21 Gy, in 3 fractions using the Cyberknife system. Primary endpoints were incidences of acute toxicities and short-term biochemical recurrence-free survival (BCRFS). Secondary endpoints included late toxicities and short-term clinical progression-free survival (CPFS).ResultsA total of 26 patients were enrolled. Twelve patients received a boost dose of 18 Gy, and the rest received 21 Gy. The Median follow-up duration was 35 months. There were no grade ≥ 3 genitourinary (GU) or gastrointestinal (GI) toxicities. Sixty-one and 4% of patients experienced grade 1–2 acute GU and GI toxicities, respectively. There were 12% late grade 1–2 GU toxicities and 8% late grade 1–2 GI toxicities. Patient-reported outcomes of urinary symptoms were aggravated after WPRT and SBRT boost. However, they resolved at 1 month and returned to the baseline level at 4 months. Three-year BCRFS was 88.1%, and CPFS was 92.3%.ConclusionsThe present study protocol demonstrated that the combination of ADT, WPRT, and SBRT boosts for high-risk prostate cancer is safe and feasible, and may reduce total treatment time to 5 weeks. Boost dose of 21 Gy in 3 fractions seems appropriate.Trial registrationClinicalTrials.gov, ID; NCT03322020 - Retrospectively registered on 26 October 2017.

Bone metabolism biomarkers (BMB) and progression-free survival (PFS) in men with metastatic hormone-sensitive prostate cancer (HSPC): SWOG S1216, a phase III trial of androgen deprivation therapy (ADT) with or without orteronel.

5523 Background: We previously reported that baseline BMB are independently prognostic for overall survival (OS) in men with castration resistant prostate cancer. We correlated BMB with outcomes in mHSPC as part of S1216, a phase III trial of ADT +/- the novel CYP17 inhibitor orteronel. Methods: Blood was obtained at study entry for bone resorption [C-telopeptide(CTx) &amp; Pyridinoline(PYD)] &amp; formation markers [C-terminal collagen propeptide(CICP) &amp; bone alkaline phosphatase(BAP)]. With prior DSMC approval, patients were sampled to mask potential treatment effect. Logistic regression was used to assess if BMB elevation above median was prognostic for a PFS event w/in 2 years across pooled study treatment arms, adjusting for baseline variables (including disease extent, PSA, age, pre-randomization ADT, &amp; presence of bone mets). An additional interaction term between BMB elevation &amp; presence of bone mets was included; if significant, separate models were developed for men +/- bone mets. Results: Of 1,313 men, 656 were included in this analysis. All 4 BMB levels were higher in men with a PFS event w/in 2 years vs. those with no PFS event. The odds ratio (OR) for a PFS event was significantly higher in men w/ elevated baseline BMB (see table). For BAP, a significant interaction between marker elevation and bone mets was seen (p = 0.003); men w/ bone mets and BAP elevation had an OR of 1.83 for a PFS event in 2 years. Conclusions: In men with newly diagnosed HSPC, elevated baseline levels of BMB were significantly associated with PFS, with about a two-fold increased risk of a progression event w/in 2 years. For CICP, CTx, &amp; PYD, this association was independent of the presence of bone metastases. Baseline BMB levels have strong prognostic value in the mHSPC context. Correlative analysis of BMB &amp; OS is planned. Clinical trial information: NCT01809691 . [Table: see text]

Phase II Trial of Enzalutamide and Androgen Deprivation Therapy with Salvage Radiation in Men with High-risk Prostate-specific Antigen Recurrent Prostate Cancer: The STREAM Trial

BackgroundSalvage external beam radiotherapy (RT) with androgen deprivation therapy (ADT) improves survival over RT in men with prostate cancer (PC) and rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP). ObjectiveTo investigate the safety and efficacy of enzalutamide concurrent with salvage RT and ADT. Design, setting, and participantsThis was a three-center prospective phase 2 single-arm trial (NCT02057939) of men with Gleason 7–10 PC and PSA recurrence within 4 yr of RP ranging from 0.2 to 4.0 ng/dl, no prior hormonal therapy, and no radiographic evidence of metastases. We enrolled 38 men; 37 completed therapy and were evaluable with testosterone recovery at 2 yr. InterventionSix months of ADT with 160 mg/d enzalutamide and 66 Gy RT to the prostate bed. Outcome measurements and statistical analysisThe primary endpoint was improved 2-yr progression-free survival (PFS) over historical controls. Secondary objectives included 3-yr PFS, safety, and patient-reported quality of life (QOL). Results and limitationsThe primary endpoint of 2-yr PFS was 65% (95% confidence interval [CI]: 47, 78) versus 51% (95% CI: 33, 67) in a trial of men with similar eligibility treated with salvage RT and adjuvant docetaxel. The 3-yr PFS was 53%. Eleven (29%) men experienced G3 toxicities, and there were no G4–5 or unexpected toxicities. QOL data suggest modest worsening of bowel, bladder, and hormonal symptoms at 3 mo, with recovery by 24 mo in most men. ConclusionsSalvage RT with enzalutamide and ADT following RP for men with PSA recurrent high-risk PC is safe and demonstrates encouraging efficacy, warranting prospective controlled phase 3 trials of ADT with or without potent androgen receptor inhibition in this curative-intent setting. Patient summaryAddition of 6 mo of oral daily enzalutamide to standard salvage radiation and hormone therapy is safe and may improve prostate cancer remission rates at 2 and 3 yr.

803P - Randomized trial of androgen deprivation therapy (ADT) + enzalutamide (Arm A) versus ADT + bicalutamide (Arm B) in metastatic hormone sensitive prostate cancer (mHSPC)

803P - Randomized trial of androgen deprivation therapy (ADT) + enzalutamide (Arm A) versus ADT + bicalutamide (Arm B) in metastatic hormone sensitive prostate cancer (mHSPC)

801P - Bone metabolism biomarkers (BMB) in hormone sensitive prostate cancer (HSPC): Results from SWOG S1216, a phase III trial of androgen deprivation therapy (ADT) +/- orteronel

801P - Bone metabolism biomarkers (BMB) in hormone sensitive prostate cancer (HSPC): Results from SWOG S1216, a phase III trial of androgen deprivation therapy (ADT) +/- orteronel

LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.

LBA3 Background: Pts with newly diagnosed mHNPC, particularly with high-risk characteristics, have a poor prognosis. ADT+docetaxel showed improved outcomes in mHNPC, but many pts are not candidates for docetaxel and may benefit from alternative therapy. AA+P is indicated for metastatic castration-resistant prostate cancer pts. LATITUDE evaluates clinical benefit of early intervention with AA+P added to ADT in newly diagnosed, high-risk mHNPC pts. Methods: 1199 pts with newly diagnosed (≤ 3 mos prior to randomization) mHNPC (ECOG PS 0-2) with ≥ 2 of 3 risk factors (Gleason ≥ 8, ≥ 3 bone lesions, measurable visceral metastases) were randomized 1:1 to ADT+AA (1 g QD) + P (5 mg QD) or ADT+PBOs of AA and P. Co-primary end points were overall survival (OS) and radiographic progression-free survival (rPFS). One rPFS (~565 events), 2 interim, and 1 final OS analyses (~426, ~554, and ~852 events) were planned. Results: At this first interim analysis (median follow-up of 30.4 mos; 406 deaths [48%]; 593 rPFS events), OS, rPFS, and all secondary end points significantly favored ADT+AA+P (Table). The IDMC unanimously recommended unblinding the study and crossing pts to ADT+AA+P. Grade 3/4 adverse events (ADT+AA+P vs ADT+PBOs) (%): hypertension (20.3 vs 10.0); hypokalemia (10.4 vs 1.3); increased ALT (5.5 vs 1.3) or AST (4.4 vs 1.5). Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. Clinical trial information: NCT01715285. [Table: see text]

LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.

LBA3 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, June 3, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial

BackgroundThe role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown in the CHAARTED trial in patients with metastatic high-volume disease (HVD). ObjectiveTo assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study. Design, setting, and participantsRandomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr. Outcome measurements and statistical analysisPrimary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume. Results and limitationsAfter a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval [CI], 49.5–73.7) and 48.6 mo (95% CI, 40.9–60.6) for ADT plus D and ADT arms, respectively (hazard ratio [HR]: 0.88 [95% CI, 0.68–1.14]; p=0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0–53.4) versus 35.1 mo (95% CI, 29.9–43.6) (HR: 0.78 [95% CI, 0.56–1.09]; p=0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5–NR) and 83.4 mo (95% CI, 61.8–NR) (HR: 1.02 [95% CI, 0.67–1.55]; p=0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3–66.8) and 41.5 mo (95% CI, 36.3–54.5), respectively (HR: 0.93 [95% CI, 0.69–1.25]; p=0.6). The bPFS (HR: 0.73 [95% CI, 0.56–0.94]; p=0.014) and rPFS (HR: 0.75 [95% CI, 0.58–0.97]; p=0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups. ConclusionsThe post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D. Patient summaryIn this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15.

A phase II trial of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for local failures or advanced prostate cancer

Long-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation. Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy. Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received. Forty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %). The treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.

Celecoxib trampled in the STAMPEDE trial

Initial results from the STAMPEDE trial of androgen deprivation therapy with and without celecoxib in patients with prostate cancer have shown that celecoxib does not confer benefit. Despite this negative finding, this multiarm, multistage trial will be informative of future clinical trial design, particularly as new agents become available for prostate cancer.

The decline and fall of RCTs

A theme for this issue is data quality. Wehbi and colleagues1 review the progress made in randomized clinical trials (RCTs) over the last few decades, particularly in prostate cancer. RCTs have increased, although they still represent a small minority of published studies. Encouragingly, almost 50% of the RCTs were led by urologists, and 7% of the RCTs worldwide were from Canada. The authors conclude with a plea for greater efforts to initiate and complete RCTs. This is laudable. The authors rightly emphasize that a randomization of patients reduces the confounding effects of selection bias. But, despite high hopes for specific initiatives, RCTs (more often than not) fail to answer the question which motivated the original trial. Biology is complex, and gives up its secrets reluctantly. Difficulties of trial design, implementation, patient and disease heterogeneity, changing epidemiology and evolving science confound the best of intentions. For example, the mother of all prostate trials, ERSPC, has not resolved the question of whether screening is warranted (although it has served to focus the discussion and clarify the issues). PLCO tried to answer the same question, but arguably the results have only confused matters. PCPT and REDUCE do not appear to have resolved the question of the preventive benefit of 5-ARIs. Randomized trials of androgen deprivation therapy have left many key questions unanswered about timing of therapy, combination therapy versus monotherapy, the importance of nadir testosterone, etc. The phenomenon, whereby a supposedly definitive trial mainly serves to raise more questions, can be observed in all urology subspecialities, and indeed throughout medicine. A disturbing trend in the area of RCTs is the change in the mandate and funding of the NCIC Clinical Trials Group. The financial basis for the NCIC CTG national trials was that most cancer centres in the country supported these trials “pro bono” due to low per-case reimbursement. This was the only way the trials could be carried out affordably. Resources were provided by the cancer centres and industry-sponsored trials generated some additional revenue to make up the shortfall. The arrangement worked well for about 30 years, but has become unfeasible due to a reduction in these sources. Cancer centres are no longer willing or can no longer afford to subsidize uneconomic clinical trial operations and the “overage” from industry-sponsored trials diminished. The NCIC CTG, recognizing this, announced that it is moving out of the domain of uneconomic large scale trials, and will, going forward, be a facilitator for pharmaceutical and other funded trials. The NCIC CTG lion has become a pussycat. Lamentably, the opportunity to do large scale trials testing the tough questions in urologic cancer will be reduced for the foreseeable future. In the current climate, there is still opportunity. Investigator-initiated trials, sponsored by industry, offer a great opportunity to carry out trials of new drugs, or established drugs seeking new indications. Pharmaceutical companies look very favourably on these proposals due to substantially reduced monitoring requirements. I’d encourage all research-oriented urologists to think about interesting drug-related questions answerable with a small-medium size trial, and propose these to potential sponsors. In the context of the controversy over the interpretation of the 2 large screening trials, the publication of the new CUA prostate cancer screening guideline in this issue is a welcome and clear statement in this perennially controversial area.2 While the controversy is far from closed, this guideline is a major step forward and will be quoted for years to come.