High-risk Biochemical Recurrence Research Articles

A bicentric retrospective study of the correlation of EAU BCR risk groups with 18F-PSMA-1007 PET/CT detection in prostate cancer biochemical recurrence

The European Association of Urology (EAU) has proposed a risk stratification for patients harboring biochemical recurrence (BCR) after radical prostatectomy: ISUP < 4 and PSA doubling time (PSAdt) > 12 months for low risk, and ISUP ≥ 4 or PSAdt ≤ 12 months for high risk. This dual-center retrospective study aims to investigate the correlation between the EAU risk stratification for BCR following radical prostatectomy and the detection rate of lesions using 18F-PSMA-1007 PET/CT. Among the 71 included patients (58 high-risk, 13 low-risk), with a median PSA level of 1.43 ng/ml, PET/CT demonstrated a significantly higher positivity in the high-risk group compared to the low-risk group (72.4% vs. 38.0%, p = 0.026). Analysis of recurrence sites revealed a similar proportion of pelvic-confined disease in both groups (24.1% vs. 23.1%, p = 0.935), but a significantly higher incidence of metastatic disease in the high-risk group (51.7% vs. 15.4%, p = 0.017), with detailed findings indicating an increased prevalence of bone metastases in the high-risk BCR group (37.8% vs. 7.7%, p = 0.048). Therefore, PSMA PET/CT offers valuable insights for treatment decisions, aligning with the evolving landscape of prostate cancer management.

How the Management of Biochemical Recurrence in Prostate Cancer Will Be Modified by the Concept of Anticipation and Incrementation of Therapy.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study.

Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase 3, randomized, double-blind, placebo-controlled study (ARASTEP).

TPS254 Background: Patients with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop BCR, defined as a prostate-specific antigen (PSA) increase without evidence of metastases on conventional imaging. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), a more effective and precise imaging method, may detect small lesions in patients with BCR. Patients with BCR at high risk of metastatic progression and who have lesions identified by PSMA PET/CT need effective treatment to delay this progression. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor, which significantly improved metastasis-free survival (MFS) and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). The ARASTEP study (NCT05794906) is designed to evaluate whether DARO plus ADT improves radiological progression-free survival (rPFS) by PSMA PET/CT vs placebo (PBO) plus ADT in patients with BCR following primary therapy and PSMA PET/CT-positive lesions. Methods: Eligible patients must have prostate cancer treated by primary RT or RP followed by adjuvant RT (ART) or salvage RT (SRT), or RP alone if ART/SRT was not appropriate, with high-risk BCR (defined as PSA doubling time [PSADT] &lt;12 months and PSA ≥0.2 ng/mL after primary RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), ≥1 PSMA PET/CT-positive lesion of prostate cancer without visible lesions on conventional imaging, and serum testosterone &gt;150 ng/dL. Approximately 750 patients from 184 sites worldwide will be randomized to oral DARO 600 mg twice daily or PBO, both with ADT, for 24 months unless, during this period, there is disease progression, unacceptable toxicity, or any other withdrawal criteria are met. Patients will suspend treatment after 24 months if PSA values are undetectable (&lt;0.2 ng/mL). Patients whose PSA values are still detectable (≥0.2 ng/mL) will continue with the study treatment until PSMA PET/CT progression. Image-guided radiotherapy or surgery is allowed within 12 weeks from randomization. Randomization is stratified by PSADT &lt;6 vs ≥6–&lt;12 months, intent to treat baseline PSMA PET/CT lesions with image-guided radiotherapy/surgery (Yes vs No) and distant ± locoregional vs locoregional-only metastases. The primary endpoint is rPFS by PSMA PET/CT, assessed by blinded independent central review (BICR). Secondary endpoints include MFS by BICR, time to CRPC, OS, quality of life, and safety. As of September 2023, 1 patient has been enrolled. Clinical trial information: NCT05794906 .

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer

BackgroundPatients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown.MethodsIn this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety.ResultsA total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P=0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.ConclusionsIn patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.)

EAU Biochemical Recurrence Risk Classification and PSA Kinetics Have No Value for Patient Selection in PSMA-Radioguided Surgery (PSMA-RGS) for Oligorecurrent Prostate Cancer.

To assess the influence of biochemical recurrence (BCR) risk groups and PSA kinetics on the outcomes of radioguided surgery against prostate-specific membrane antigen (PSMA-RGS). Currently, neither BCR risk group nor PSA doubling time (PSA-DT), or PSA velocity (PSA-V) are actively assigned or relevant for counseling prior to PSMA-RGS. We retrospectively analyzed PSMA-RGS cases for oligorecurrent prostate cancer between 2014 and 2023. BCR risk groups, PSA-DT, and PSA-V were analyzed as predictors for complete biochemical response (cBR, PSA < 0.2 ng/mL), BCR-free, and therapy-free survival (BCRFS, TFS). Of 374 included patients, only 21/374 (6%) and 201/374 (54%) were classified as low- and high-risk BCR (no group assignment possible in 152/374, 41%). A total of 13/21 (62%) patients with low- and 120/201 (60%) with high-risk BCR achieved cBR (p = 1.0). BCR classification was no predictor for BCRFS (HR:1.61, CI: 0.70-3.71, p = 0.3) or subsequent TFS (HR:1.07, CI: 0.46-2.47, p = 0.9). A total of 47/76 (62%) patients with PSA-DT ≤ 6 mo and 50/84 (60%) with PSA-DT > 6 mo achieved cBR (p = 0.4). PSA-DT was not associated with cBR (OR: 0.99, CI: 0.95-1.03, p = 0.5), BCRFS (HR: 1.00, CI: 0.97-1.03, p = 0.9), or TFS (HR: 1.02, CI: 0.99-1.04, p = 0.2). Consistent negative findings were recorded for PSA-V. The BCR risk groups and PSA kinetics do not predict the oncological success of PSMA-RGS performed at low absolute PSA values. Indolent low-risk BCR is rarely treated by PSMA-RGS.

1766MO Health-related quality of life (HRQoL) in nonmetastatic hormone-sensitive prostate cancer (nmHSPC) patients (pts) with high-risk biochemical recurrence (BCR) from the EMBARK study

1766MO Health-related quality of life (HRQoL) in nonmetastatic hormone-sensitive prostate cancer (nmHSPC) patients (pts) with high-risk biochemical recurrence (BCR) from the EMBARK study

1841TiP Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase III, randomized, double-blind, placebo-controlled study (ARASTEP)

1841TiP Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase III, randomized, double-blind, placebo-controlled study (ARASTEP)

1777P Enzalutamide (enza) monotherapy for the treatment (tx) of prostate cancer with high-risk biochemical recurrence (BCR): EMBARK secondary endpoints

1777P Enzalutamide (enza) monotherapy for the treatment (tx) of prostate cancer with high-risk biochemical recurrence (BCR): EMBARK secondary endpoints

European Association of Urology Biochemical Recurrence Risk Classification as a Decision Tool for Salvage Radiotherapy—A Multicenter Study

BackgroundThe European Association of Urology (EAU) has proposed a risk stratification for patients harboring biochemical recurrence (BCR) after radical prostatectomy (RP). ObjectiveTo assess whether this risk stratification helps in choosing patients for salvage radiotherapy (SRT). Design, setting, and participantsAnalyses of 2379 patients who developed BCR after RP (1989–2020), within ten European high-volume centers, were conducted. Early and late SRT were defined as SRT delivered at prostate-specific antigen values <0.5 and ≥0.5 ng/ml, respectively. Outcome measurements and statistical analysisMultivariable Cox models tested the effect of SRT versus no SRT on death and cancer-specific death. The Simon-Makuch method tested for survival differences within each risk group. Results and limitationsOverall, 805 and 1574 patients were classified as having EAU low- and high-risk BCR. The median follow-up was 54 mo after BCR for survivors. For low-risk BCR, 12-yr overall survival was 87% versus 78% (p = 0.2) and cancer-specific survival was 100% versus 96% (p = 0.2) for early versus no SRT. For high-risk BCR, 12-yr overall survival was 81% versus 66% (p < 0.001) and cancer-specific survival was 98% versus 82% (p < 0.001) for early versus no SRT. In multivariable analyses, early SRT decreased the risk for death (hazard ratio [HR]: 0.55, p < 0.01) and cancer-specific death (HR: 0.08, p < 0.001). Late SRT was a predictor of cancer-specific death (HR: 0.17, p < 0.01) but not death (p = 0.1). ConclusionsImproved survival was recorded within the high-risk BCR group for patients treated with early SRT compared with those under observation. Our results suggest recommending early SRT for high-risk BCR men. Conversely, surveillance might be suitable for low-risk BCR, since only nine patients with low-risk BCR died from prostate cancer during follow-up. Patient summaryThe impact of salvage radiotherapy (SRT) on cancer-specific outcomes stratified according to the European Association of Urology biochemical recurrence (BCR) risk classification was assessed. While men with high-risk BCR should be offered SRT, surveillance might be a suitable option for those with low-risk BCR.

LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer

LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer

LBA02-09 EMBARK: A PHASE 3 RANDOMIZED STUDY OF ENZALUTAMIDE OR PLACEBO PLUS LEUPROLIDE ACETATE AND ENZALUTAMIDE MONOTHERAPY IN HIGH-RISK BIOCHEMICALLY RECURRENT PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023LBA02-09 EMBARK: A PHASE 3 RANDOMIZED STUDY OF ENZALUTAMIDE OR PLACEBO PLUS LEUPROLIDE ACETATE AND ENZALUTAMIDE MONOTHERAPY IN HIGH-RISK BIOCHEMICALLY RECURRENT PROSTATE CANCER Neal D. Shore, Murilo de Almeida Luz, Ugo De Giorgi, Martin Gleave, Geoffrey T. Gotto, Gabriel P. Haas, Miguel Ramirez-Backhaus, Antti Rannikko, Jamal Tarazi, Swetha Sridharan, Jennifer Sugg, Yiyun Tang, Ronald F. Tutrone, Balaji Venugopal, Arnauld Villers, Henry H. Woo, Fabian Zohren, and Stephen J. Freedland Neal D. ShoreNeal D. Shore More articles by this author , Murilo de Almeida LuzMurilo de Almeida Luz More articles by this author , Ugo De GiorgiUgo De Giorgi More articles by this author , Martin GleaveMartin Gleave More articles by this author , Geoffrey T. GottoGeoffrey T. Gotto More articles by this author , Gabriel P. HaasGabriel P. Haas More articles by this author , Miguel Ramirez-BackhausMiguel Ramirez-Backhaus More articles by this author , Antti RannikkoAntti Rannikko More articles by this author , Jamal TaraziJamal Tarazi More articles by this author , Swetha SridharanSwetha Sridharan More articles by this author , Jennifer SuggJennifer Sugg More articles by this author , Yiyun TangYiyun Tang More articles by this author , Ronald F. TutroneRonald F. Tutrone More articles by this author , Balaji VenugopalBalaji Venugopal More articles by this author , Arnauld VillersArnauld Villers More articles by this author , Henry H. WooHenry H. Woo More articles by this author , Fabian ZohrenFabian Zohren More articles by this author , and Stephen J. FreedlandStephen J. Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003361.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Within 10 years of following definitive therapy for prostate cancer, ∼20–50% of patients experience biochemical recurrence (BCR) characterized by rising prostate-specific antigen (PSA) levels. Given that novel hormone therapy plus androgen deprivation therapy has shown improved survival in metastatic hormone-sensitive prostate cancer, the objective of EMBARK was to evaluate the efficacy and safety of enzalutamide plus leuprolide acetate (LA) and enzalutamide monotherapy, earlier in the disease course in patients with high-risk BCR. METHODS: EMBARK (NCT02319837) is a randomized, phase 3 study of patients with BCR after local therapy considered high-risk: PSA doubling time ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP)±postoperative RT. Patients were randomized (1:1:1) to enzalutamide 160 mg/day plus LA (double-blind), placebo plus LA (double-blind), or enzalutamide monotherapy (open-label). LA 22.5 mg was administered every 12 weeks. If the PSA was <0.2 ng/mL at Week 36, therapy was stopped and restarted when PSA was ≥2 ng/mL for patients with primary RP, and ≥5 ng/mL for patients without RP. The primary endpoint, determined by blinded, independent central review, was metastasis-free survival (MFS) with enzalutamide plus LA vs placebo plus LA. Key secondary endpoints were MFS of enzalutamide monotherapy vs placebo plus LA, time to PSA progression, time to antineoplastic therapy, and overall survival of enzalutamide monotherapy or enzalutamide plus LA vs placebo plus LA. RESULTS: A total of 1068 patients were eligible and randomized in the study. The primary hypothesis was that treatment intensification with enzalutamide is associated with improved MFS vs placebo. Results will be analyzed to determine if enzalutamide in combination with LA and enzalutamide monotherapy significantly improved MFS vs placebo with LA and demonstrated an acceptable safety profile consistent with previous randomized controlled trials. Data analysis is ongoing and detailed outcomes will be provided in the late-breaking submission. CONCLUSIONS: The results will address the hypothesis that in patients with high-risk BCR, enzalutamide plus LA and enzalutamide monotherapy were associated with improved MFS vs placebo plus LA. Source of Funding: Pfizer Inc. and Astellas Pharma Inc © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1190 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Murilo de Almeida Luz More articles by this author Ugo De Giorgi More articles by this author Martin Gleave More articles by this author Geoffrey T. Gotto More articles by this author Gabriel P. Haas More articles by this author Miguel Ramirez-Backhaus More articles by this author Antti Rannikko More articles by this author Jamal Tarazi More articles by this author Swetha Sridharan More articles by this author Jennifer Sugg More articles by this author Yiyun Tang More articles by this author Ronald F. Tutrone More articles by this author Balaji Venugopal More articles by this author Arnauld Villers More articles by this author Henry H. Woo More articles by this author Fabian Zohren More articles by this author Stephen J. Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Survival analysis of the randomized phase II trial to investigate androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.

5076 Background: LACOG 0415 is a phase II, open-label, clinical trial evaluating ADT-free alternatives for advanced castration sensitive prostate cancer (CSPC). Methods: Patients with locally advanced, high-risk biochemical recurrence or metastatic CSPC were randomized (1:1:1) to receive ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA), or apalutamide with AAP (APA+AAP). The primary endpoint of the trial was the proportion of patients who achieved PSA≤0.2 ng/mL level at week 25. Patients without disease-progression and with clinical benefit after week 25 were allowed to maintain treatment at the discretion of physicians. Herein, we presented the outcomes of 2 year-overall survival (2y-OS) and time-to-treatment failure (TTF). The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were randomized to the ADT+AAP (n = 42), APA (n = 42), and APA+AAP (n = 44) arms. At week 25, PSA≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in the ADT+AAP, APA, and APA+AAP arms, respectively. 110 patients continued treatment after week 25. At the 2-year visit, 80 (62.5%) patients remained on the study medication. Median TTF was 24.0 months (95%CI 23.3 - 24.0) with ADT+AAP, 24.0 months (95%CI not estimated) with APA, and 24.0 months (95%CI 13.0-24.0) with APA+AAP. The main reasons for treatment discontinuation were disease progression (n = 8, 6.3%), toxicity (n = 10, 7.8%), death (n = 6, 4.7%), withdrawal (n = 4, 3.1%), and other (n = 19, 14.8%). The estimated proportion of patients who were alive at 2 years (2y-OS rate) was 92.5% (95%CI 84.3-100) with ADT+AAP, 87.9% (95%CI 77.9-97.8) with APA, and 92.7% (95%CI 84.8-100) with APA+AAP (p = 0.5926). 2y-OS was 92.9% (95% CI 85.3 - 96.2) in patients with PSA ≤ 0.2 ng/mL at week 25, while 2y-OS was 85.0% (95% CI 72.9-97.1) in patients with PSA &gt; 0.2 ng/mL at week 25 (p = 0.1250). Conclusions: Patients with advanced CSPC treated with ADT+AAP, APA, or APA+AAP had high rates of PSA response and favorable 2y-OS. PSA ≤ 0.2 ng/mL at week 25 seems to be a surrogate prognostic predictor of OS in advanced CSPC. In the overall sample, patients with PSA ≤ 0.2 ng/mL at week 25 had higher 2y-OS rate than those with PSA &gt; 0.2 ng/mL at week 25 (92.9% vs. 85.0%), however without statistical significance. Clinical trial information: NCT02867020.

Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy

BackgroundPhase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. ObjectiveTo compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. Design, setting, and participantsPatients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. InterventionPatients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. Outcome measurements and statistical analysisThe primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. Results and limitationsFor the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1–17%], arm 2: 17.1% [95% CI: 7–32%], arm 3: 11.9% [95% CI: 4–26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9–36.1]) relative to degarelix (52.9 wk [95% CI: 49.0–56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. ConclusionsRates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. Patient summaryWe evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.

A phase 2 randomized clinical trial of abiraterone plus ADT, apalutamide, or abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone levels (LACOG 0415)

BackgroundAndrogen deprivation therapy (ADT) combined with apalutamide, abiraterone acetate plus prednisone, enzalutamide, or docetaxel are the standard treatments for advanced castration-sensitive prostate cancer (CSPC). We investigated ADT-free alternatives for advanced CSPC. Patients and methodsLACOG 0415 is a phase 2, open-label, non-comparative, randomized trial. Patients with advanced CSPC were randomized (1:1:1) to receive goserelin plus abiraterone acetate and prednisone (ADT plus AAP arm), apalutamide (APA arm), or apalutamide plus abiraterone acetate and prednisone (APA plus AAP arm). The primary endpoint was the proportion of patients with PSA of ≤0.2 ng/mL at week 25 in the modified intention-to-treat population. Safety analyses were performed in all patients with at least one dose of the study drug. ResultsOf 128 randomized patients, 120 patients were evaluable for PSA response at week 25; 17.2% had a high-risk biochemical recurrence, 8.6% had locally advanced disease, and 74.2% had distant metastases. At week 25, PSA of ≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%–87.6%), 60.0% (95%CI 43.3%–75.1%), and 79.5% (95%CI 63.5%–90.7%) of patients in ADT plus AAP, APA, and APA plus AAP arms, respectively. PSA decline of ≥80% was observed in 100%, 90.0%, and 97.4%, respectively. Grade 3–4 AEs were observed in 31.0%, 21.4% and 36.4%, respectively. Testosterone levels increased significantly in the APA arm and decreased significantly in ADT plus AAP and APA plus AAP arms. ConclusionsADT-free alternatives provide a high PSA response in advanced CSPC, although the APA arm did not reach the expected rate of PSA of ≤0.2 ng/mL at week 25. These results warrant further investigation of ADT-free treatments as alternatives in advanced CSPC. Source study registrationClinicalTrials.govNCT02867020.

PSMA PET Validates Higher Rates of Metastatic Disease for European Association of Urology Biochemical Recurrence Risk Groups: An International Multicenter Study.

The European Association of Urology (EAU) prostate cancer guidelines panel recommends risk groups for biochemical recurrence (BCR) of prostate cancer to identify men at high risk of progression or metastatic disease. The rapidly growing availability of PSMA-directed PET imaging will impact prostate cancer staging. We determined the rates of local and metastatic disease in BCR and biochemical persistence (BCP) of prostate cancer stratified by EAU BCR risk groups and BCP. Methods: Patients with BCR or BCP were enrolled under the same prospective clinical trial protocol conducted at 3 sites (n = 1,777 [91%]: UCLA, n = 662 [NCT02940262]; University of California San Francisco, n = 508 [NCT03353740]; University of Michigan, n = 607 [NCT03396874]); 183 patients with BCP from the Universities of Essen, Bologna, and Munich were included retrospectively. Patients with BCR had to have sufficient data to determine the EAU risk score. Multivariate, binomial logistic regression models were applied to assess independent predictors of M1 disease. Results: In total, 1,960 patients were included. Post-radical prostatectomy EAU BCR low-risk, EAU BCR high-risk, and BCP groups yielded distant metastatic (M1) detection in 43 of 176 (24%), 342 of 931 (37%), and 154 of 386 (40%) patients. For postradiotherapy EAU BCR low-risk and EAU BCR high-risk groups, the M1 detection rate was 113 of 309 (37%) and 110 of 158 (70%), respectively. BCP, high-risk BCR, and higher levels of serum prostate-specific antigen were significantly associated with PSMA PET M1 disease in multivariate regression analysis. PSMA PET revealed no disease in 25% and locoregional-only disease in 33% of patients with post-radical prostatectomy or postradiotherapy EAU BCR high risk. Conclusion: Our findings support the new EAU classification; EAU BCR high-risk groups have higher rates of metastatic disease on PSMA PET than do the low-risk groups. Discordant subgroups, including metastatic disease in low-risk patients and no disease in high-risk patients, warrant inclusion of PSMA PET stage to refine risk assessment.

The European Association of Urology Biochemical Recurrence Risk Groups Predict Findings on PSMA PET in Patients with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.

Our purpose was to evaluate the association of a new biochemical recurrence (BCR) risk stratification system with PSMA-targeted PET/CT findings. Methods: Two prospective studies that included patients with BCR were pooled. Findings on PSMA PET were catalogued. Patients were characterized according to the European Association of Urology BCR risk categories. Univariable and multivariable analyses were performed by logistic regression. Results: In total, 145 patients were included (45 low-risk and 100 high-risk). High-risk BCR patients had a higher positive rate than low-risk patients (82.0% vs. 48.9%; P < 0.001) and reached independent predictor status for positive PSMA PET/CT scan results on multivariable logistic regression (odds ratio, 6.73; 95% CI, 2.41-18.76; P < 0.001). The area under the curve using the combination of BCR risk group and prostate-specific antigen was higher than that using prostate-specific antigen alone (0.834 vs. 0.759, P = 0.015). Conclusion: The European Association of Urology BCR risk groups define the candidates who can most benefit from a PSMA PET/CT scan when BCR occurs.

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.

Health-related quality-of-life (HRQoL) analysis from a randomized phase II trial of androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.

64 Background: LACOG0415 is a 3-arm randomized trial evaluating ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA) or apalutamide with AAP (APA+AAP) for patients with locally-advanced, high-risk biochemical recurrence or metastatic castration-sensitive prostate cancer (ASCO 2020). In this trial, ADT+AAP and APA+AAP achieved the primary endpoint of percentage of patients with PSA ≤ 0.2 ng/mL at week 25. Apalutamide alone showed a high PSA decline &gt; 50% rate, but did not achieve the pre-specified PSA threshold. Here we report patient-reported outcome data using Functional Assessment of Cancer Therapy-Prostate (FACT-P). Methods: HRQoL was measured in the overall population using the FACT-P questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing (EWB), social/family wellbeing (SFWB), and prostate cancer subscale (PCS). Scores for each patient were measured at baseline and every four weeks until week 25. Questionnaire completion was defined as ≥ 1 question answered at an assessment time point. Analysis of HRQoL change from baseline and deterioration included only patients with baseline and ≥ 1 postbaseline score. Differences greater than 10-points in FACT-P total score and differences greater than 3-points in PWB, FWB, EWB, SFWB, and PCS scores were considered clinically significant. The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were included in LACOG0415 trial and 122 of them completed the HRQoL assessments (ranging from 95.3% at baseline to 79.7% at week 25). FACT-P and all subscales scores were similar for all three arms at baseline. There were no meaningful differences in FACT-P scores at baseline and at week 25 between the 3 arms. The subscales scores also showed no statistically differences at baseline and at week 25. Time to FACT-P deterioration did not show any statistically difference between three arms ( P=0.3371). Conclusions: ADT free alternatives with APA alone or APA+AAP did not show meaningful differences in HRQoL in patients with advanced castration-sensitive prostate cancer compared to ADT+AAP. The short follow-up period limited the ability to explore differences in HRQoL after 25 weeks. Larger studies with longer follow-up are needed to further evaluate HRQoL with ADT-free strategies. Clinical trial information: NCT02867020. [Table: see text]

Detection of Recurrent Prostate Cancer With 18F-Fluciclovine PET/MRI.

ObjectiveSimultaneous PET/MRI combines soft-tissue contrast of MRI with high molecular sensitivity of PET in one session. The aim of this prospective study was to evaluate detection rates of recurrent prostate cancer by 18F-fluciclovine PET/MRI.MethodsPatients with biochemical recurrence (BCR) or persistently detectable prostate specific antigen (PSA), were examined with simultaneous 18F-fluciclovine PET/MRI. Multiparametric MRI (mpMRI) and PET/MRI were scored on a 3-point scale (1-negative, 2-equivocal, 3-recurrence/metastasis) and detection rates (number of patients with suspicious findings divided by total number of patients) were reported. Detection rates were further stratified based on PSA level, PSA doubling time (PSAdt), primary treatment and inclusion criteria (PSA persistence, European Association of Urology (EAU) Low-Risk BCR and EAU High-Risk BCR). A detailed investigation of lesions with discrepancy between mpMRI and PET/MRI scores was performed to evaluate the incremental value of PET/MRI to mpMRI. The impact of the added PET acquisition on further follow-up and treatment was evaluated retrospectively.ResultsAmong patients eligible for analysis (n=84), 54 lesions were detected in 38 patients by either mpMRI or PET/MRI. Detection rates were 41.7% for mpMRI and 39.3% for PET/MRI (score 2 and 3 considered positive). There were no significant differences in detection rates for mpMRI versus PET/MRI. Disease detection rates were higher in patients with PSA≥1ng/mL than in patients with lower PSA levels but did not differ between patients with PSAdt above versus below 6 months. Detection rates in patients with primary radiation therapy were higher than in patients with primary surgery. Patients categorized as EAU Low-Risk BCR had a detection rate of 0% both for mpMRI and PET/MRI. For 15 lesions (27.8% of all lesions) there was a discrepancy between mpMRI score and PET/MRI score. Of these, 10 lesions scored as 2-equivocal by mpMRI were changed to a more definite score (n=4 score 1 and n=6 score 3) based on the added PET acquisition. Furthermore, for 4 of 10 patients with discrepancy between mpMRI and PET/MRI scores, the added PET acquisition had affected the treatment choice.ConclusionCombined 18F-fluciclovine PET/MRI can detect lesions suspicious for recurrent prostate cancer in patients with a range of PSA levels. Combined PET/MRI may be useful to select patients for appropriate treatment, but is of limited use at low PSA values or in patients classified as EAU Low-Risk BCR, and the clinical value of 18F-fluciclovine PET/MRI in this study was too low to justify routine clinical use.

A Novel Apoptosis-Related Gene Signature Predicts Biochemical Recurrence of Localized Prostate Cancer After Radical Prostatectomy.

Background: Nowadays, predictions of biochemical recurrence (BCR) in localized prostate cancer (PCa) patients after radical prostatectomy (RP) are mainly based on clinical parameters with a low predictive accuracy. Given the critical role of apoptosis in PCa occurrence and progression, we aimed to establish a novel predictive model based on apoptosis-related gene signature and clinicopathological parameters that can improve risk stratification for BCR and assist in clinical decision-making.Methods: Expression data and corresponding clinical information were obtained from four public cohorts, one from The Cancer Genome Atlas (TCGA) dataset and three from the Gene Expression Omnibus (GEO) dataset. Weighted gene co-expression network analysis (WGCNA) was performed to identify candidate modules closely correlated to BCR, and univariate and multivariate Cox regression analyses were utilized to build the gene signature. Time-dependent receiver operating curve (ROC) and Kaplan–Meier (KM) survival analysis were used to assess the prognostic value. Finally, we analyzed the expression of genes in the signature and validated the results using quantitative real-time PCR (qRT-PCR).Results: The novel gene signature we established exhibited a high prognostic value and was able to act as an independent risk factor for BCR [Training set: P < 0.001, hazard ratio (HR) = 7.826; Validation set I: P = 0.006, HR = 2.655; Validation set II: P = 0.003, HR = 4.175; Validation set III: P < 0.001, HR = 3.008]. Nomogram based on the gene signature and clinical parameters was capable of distinguishing high-risk BCR patients. Additionally, functional enrichment analysis showed several enriched pathways and biological processes, which might help reveal the underlying mechanism. The expression results of qRT-PCR were consistent with TCGA results.Conclusion: The apoptosis-related gene signature could serve as a powerful predictor and risk factor for BCR in localized PCa patients after RP.