Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Attard, Gerhardt; Murphy, Laura; Clarke, Noel W.; Sachdeva, Ashwin; Jones, Craig; Hoyle, Alex; Cross, William; Jones, Robert J.; Parker, Christopher; Gillessen, Silke; Cook, Adrian; Brawley, Christopher D.; Gilson, Clare; Rush, Hannah; Abdel-Aty, Hoda; Amos, Claire; Murphy, Claire; Chowdhury, Simon; Russell, John M.; Parkar, Nazia; Pugh, Cheryl; Díaz-Montaña, Carlos; Saxby, Helen; Pedley, Ian; O’Sullivan, Joe M.; Birtle, Alison; Gale, Joanna; Srihari, Narayanan; Thomas, C.; Wagstaff, John; Gray, Emma; Alzouebi, Mymoona; Parikh, Omi; Robinson, Angus; Montazeri, A; Wylie, James; Cathomas, Richard; Brown, Michael D.; Jain, Yatin; Dearnaley, David P.; Mason, Malcolm David; Gilbert, Duncan C.; Langley, Ruth E.; Millman, Robin; Matheson, David; Sydes, M; Brown, Louise; Parmar, Mahesh; James, Nicholas D.; Jones, Elin; Glen, Hilary; McGovern, Ursula; Shaffer, Richard; Beresford, Mark; Malik, Zafar; Zarkar, Anjali; Porfiri, Emilio; Fackrell, David; Lee, Ling; Brock, Sue; Bahl, Amit; Smith-Howell, Mike; Woodward, Cathryn; Phan, Mau-Don; Mazhar, Danish; Narahari, Krishna; Tanguay, Jacob; Hamid, Abdel; Ibrahim, Azman; Muthukumar, D.; Simms, Matthew; Worlding, Jane; Kagzi, M.; Das, Prantik; Pezaro, Carmel; Sivoglo, Virgil; Masters, B.; Keng-Koh, Pek; McLaren, Duncan; Gupta, Nishi; Sheehan, Denise; Boussios, Stergios; Taylor, Henry M.; Graham, John D.; Perna, Carla; Melcher, L.; Grant, Warren; Hyde, Katherine; Sabharwal, Ami; Hofmann, Uschi; Dealey, Robert; McPhail, Neil; Brierly, R.D.; Brown, Simon; Sidek, Norma; Whelan, Peter; Sreenivasan, Thiagarajan; Robson, Peter; Rudman, Sarah; Vivekanandan, Sindu; Mullessey, Vinod; Needleman, Sarah; Vilarino-Varela, Maria; Khoo, Vincent; Tipples, K. H.; Afshar, Mehran; Falconer, Alison; Brulinski, P.; Sangar, Vijay; Peedell, C.; Hoskin, Peter; Mullassery, Viwod; Sundar, Santhanam; Khan, Yakhub; Conroy, Ruth; Protheroe, Andrew; Carser, Judith; Rogers, Paul; Tarver, Kathryn; Gibbs, Stephanie; Khan, Mohammad Muneeb; Hingorani, Mohan; Crabb, Simon J.; Alameddine, Manal; Bhalla, Neeraj; Manetta, Caroline; Hughes, Robert J.; Logue, John P; Leaning, Darren; Vengalil, Salil; Azzabi, Ashraf; Ford, Daniel; Walker, Georgina; Ahmed, Shaheen; Khan, Omar; Chan, Andrew; Ahmed, Imtiaz; Hilman, Serena; Douglas, Fiona; Kumar, Anil; Tran, Anna; Paisey, Sangeeta; Sayers, Ian; Capaldi, Lisa; Nikapota, Ashok; Bloomfield, David; Porter, Tim; Joseph, Joji; Rentsch, Cyrill A.; Mestre, Ricardo Pereira; Ricevuto, Enrico; Beyer, Jörg; Borner, Markus; Strebel, Raeto T.; Berthold, Dominik R.; Engeler, Daniel S.; John, Hubert; Popescu, Răzvan; Dürr, Donat

doi:10.1016/s1470-2045(23)00148-1

Cited by 41 publications

(16 citation statements)

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“…Notably, patients with pT3b disease were significantly less likely to achieve and maintain undetectable PSA levels. These findings corroborate the prognostic value of primary tumor staging in predicting recurrence and align with previous studies highlighting the importance of local tumor stage in adverse postoperative outcomes especially among pN1 patients ( 18 ). While it is widely recognized that patients with unfavorable characteristics are more apt to benefit from adjuvant therapies, our analysis revealed that a substantial segment of patients, despite possessing such adverse factors as elevated Gleason scores and seminal vesicle invasion, successfully achieved and maintained undetectable levels of ultrasensitive PSA.…”

Section: Discussionsupporting

confidence: 90%

Ultrasensitive PSA: rethinking post-surgical management for node positive prostate cancer

Aguiar,

Li,

et al. 2024

Front. Oncol.

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IntroductionClinicians may offer patients with positive lymph nodes (pN1) and undetectable PSA following surgery for prostate cancer either observation or adjuvant therapy based on AUA, EAU, and NCCN guidelines considering standard PSA detection thresholds of <0.1ng/ml. Here we sought to investigate the outcomes of pN1 patients in the era of ultrasensitive PSA testing.MethodsWe queried the Northwestern Electronic Data Warehouse for patients with prostate cancer who were pN1 at radical prostatectomy and followed with ultrasensitive PSA. Patients receiving neoadjuvant treatment were excluded. We compared clinical characteristics including age, race, pre-operative PSA, Gleason grade, tumor stage, surgical margins, and nodal specimens to identify factors associated with achievement and maintenance of an undetectable PSA (defined as <0.01 ng/mL). Statistics were performed using t-test, Mann-Whitney U test, chi-squared analysis, and logistic regression with significance defined as p<0.05.ResultsFrom 2018-2023, 188 patients were included. Subsequently, 39 (20.7%) had a PSA decline to undetectable levels (<0.01 ng/mL) post-operatively at a median time of 63 days. Seven percent of these men (3/39) were treated with adjuvant RT + ADT with undetectable PSA levels. 13/39 (33.3%) had eventual rises in PSA to ≥0.01 ng/mL for which they underwent salvage RT with ADT. Overall, 23/39 (59%) patients achieved and maintained undetectable PSA levels without subsequent therapy at median follow-up of 24.2 mo. Compared to patients with PSA persistence after surgery or elevations to detectable levels (≥0.01 ng/mL), patients who achieved and maintained undetectable levels had lower Gleason grades (p=0.03), lower tumor stage (p<0.001), fewer positive margins (p=0.02), and fewer involved lymph nodes (p=0.02). On multivariable analysis, only primary tumor (pT) stage was associated with achieving and maintaining an undetectable PSA; pT3b disease was associated with a 6.6-fold increased chance of developing a detectable PSA (p=0.03).ConclusionUltrasensitive PSA can aid initiation of early salvage therapy for lymph node positive patients after radical prostatectomy while avoiding overtreatment in a significant subset. 20% of patients achieved an undetectable PSA and over half of this subset remained undetectable after 2 years.

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Section: Discussionsupporting

confidence: 90%

Ultrasensitive PSA: rethinking post-surgical management for node positive prostate cancer

Aguiar,

Li,

et al. 2024

Front. Oncol.

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“…10 Over the last several years, trial data in metastatic castration-resistant prostate cancer (the ACIS trial; Alliance A031201) and nonmetastatic, hormone-sensitive prostate cancer (STAMPEDE; ClinicalTrials.gov identifier NCT00268476) did not demonstrate improved overall survival or MFS, respectively, using dual-ARSI therapy compared with ARSI monotherapy plus ADT. [21][22][23] In aggregate, these data highlight the limited role for dual ARSI in prostate cancer.…”

Section: Discussionmentioning

confidence: 88%

Postradical prostatectomy prostate‐specific antigen outcomes after 6 versus 18 months of perioperative androgen‐deprivation therapy in men with localized, unfavorable intermediate‐risk or high‐risk prostate cancer: Results of part 2 of a randomized phase 2 trial

McKay,

Xie,

Yang

et al. 2024

Cancer

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BackgroundPatients with localized, unfavorable intermediate–risk and high‐risk prostate cancer have an increased risk of relapse after radical prostatectomy (RP). The authors previously reported on part 1 of this phase 2 trial testing neoadjuvant apalutamide, abiraterone, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. The results demonstrated favorable pathologic responses (tumor <5 mm) in 20.3% of patients (n = 24 of 118). Herein, the authors report the results of part 2.MethodsFor part 2, patients were randomized 1:1 to receive either AAPL for 12 months (arm 2A) or observation (arm 2B), stratified by neoadjuvant therapy and pathologic tumor classification. The primary end point was 3‐year biochemical progression‐free survival. Secondary end points included safety and testosterone recovery (>200 ng/dL).ResultsOverall, 82 of 118 patients (69%) enrolled in part 1 were randomized to part 2. A higher proportion of patients who were not randomized to adjuvant therapy had a favorable prostatectomy pathologic response (32.3% in nonrandomized patients compared with 17.1% in randomized patients). In the intent‐to‐treat analysis, the 3‐year biochemical progression‐free survival rate was 81% for arm 2A and 72% for arm 2B (hazard ratio, 0.81; 90% confidence interval, 0.43–1.49). Of the randomized patients, 81% had testosterone recovery in the AAPL group compared with 95% in the observation group, with a median time to recovery of <12 months in both arms.ConclusionsIn this study, because 30% of patients declined adjuvant treatment, part B was underpowered to detect differences between arms. Future perioperative studies should be biomarker‐directed and include strategies for investigator and patient engagement to ensure compliance with protocol procedures.

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“…Studies investigated SOC used with ARSI monotherapy or combined with another ARSI or docetaxel. The following agents were combined with SOC therapy: abiraterone acetate and prednisolone (herein referred to as abiraterone acetate) (n = 9), abiraterone acetate and docetaxel (n = 1), enzalutamide alone (n = 9), abiraterone acetate and enzalutamide (n = 2), darolutamide alone (n = 1), darolutamide and docetaxel (n = 1), and apalutamide alone (n = 2) were studied. Of the 24 eligible studies, 18 reported CV events (75%): only 16 reported grade 3 or higher CV events (67%).…”

Section: Resultsmentioning

confidence: 99%

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer

El-Taji,

Taktak,

Jones

et al. 2024

JAMA Oncol

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ImportanceCardiovascular (CV) events remain a substantial cause of mortality among men with advanced and metastatic prostate cancer (PCa). The introduction of novel androgen receptor signaling inhibitors (ARSI) has transformed the treatment landscape of PCa in recent years; however, their associated CV toxic effects remains unclear.ObjectiveTo assess the incidence of CV events with addition of ARSI to standard of care (SOC) in locally advanced (M0) and metastatic (M1) PCa.Data SourcesSystematic searches of PubMed, Scopus, Web of Science, EMBASE, and ClinicalTrials.gov were performed from inception up to May 2023.Study SelectionRandomized clinical trials of ARSI agents (abiraterone, apalutamide, darolutamide, enzalutamide) that reported CV events among individuals with M0 and M1, hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC).Data Extraction and SynthesisA systematic review was performed in accordance with PRISMA guidance. Two authors screened and independently evaluated studies eligible for inclusion. Data extraction and bias assessment was subsequently performed.Main Outcomes and MeasuresA random-effects meta-analysis was performed to estimate risk ratios for the incidence of all grade and grade 3 or higher CV events (primary outcomes), in addition to hypertension, acute coronary syndrome (ACS), cardiac dysrhythmia, CV death, cerebrovascular event, and venous thromboembolism (secondary outcomes). Sources of heterogeneity were explored using meta-regression.ResultsThere were 24 studies (n = 22 166 patients; median age range, 63-77 years; median follow-up time range, 3.9-96 months) eligible for inclusion. ARSI therapy was associated with increased risk of all grade CV event (risk ratio [RR], 1.75; 95% CI, 1.50-2.04; P &lt; .001) and grade 3 or higher CV events (RR, 2.10; 95%, 1.72-2.55; P &lt; .001). ARSI therapy also was associated with increased risk for grade 3 or higher events for hypertension (RR, 2.25; 95% CI, 1.74-2.90; P &lt; .001), ACS (RR, 1.93; 95% CI, 1.43-1.60; P &lt; .01), cardiac dysrhythmia (RR, 1.64; 95% CI, 1.23-2.17; P &lt; .001), cerebrovascular events (RR, 1.86; 95% CI, 1.34-2.59; P &lt; .001) and for CV-related death (RR, 2.02; 95% CI, 1.32-3.10; P = .001). Subgroup analysis demonstrated increased risk of all CV events across the disease spectrum (M0 HSPC: RR, 2.26; 95% CI, 1.36-3.75; P = .002; M1 HSPC: RR, 1.85; 95% CI, 1.47-2.31; P &lt; .001; M0 CRPC: RR, 1.79; 95% CI, 1.13-2.81; P = .01; M1 CRPC: RR, 1.46; 95% CI, 1.16-1.83; P = .001).Conclusions and RelevanceThis systematic review and meta-analysis found that the addition of ARSIs to traditional ADT was associated with increased risk of CV events across the prostate cancer disease spectrum. These results suggest that patients with prostate cancer should be advised about and monitored for the potential of increased risk of CV events with initiation of ARSI therapy alongside conventional hormonal therapy.

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Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Cited by 41 publications

References 24 publications

Ultrasensitive PSA: rethinking post-surgical management for node positive prostate cancer

Ultrasensitive PSA: rethinking post-surgical management for node positive prostate cancer

Postradical prostatectomy prostate‐specific antigen outcomes after 6 versus 18 months of perioperative androgen‐deprivation therapy in men with localized, unfavorable intermediate‐risk or high‐risk prostate cancer: Results of part 2 of a randomized phase 2 trial

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer

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