Abiraterone Acetate Plus Prednisone Research Articles

Blood biomarkers and association with clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC): prespecified longitudinal analysis from the ACIS study of apalutamide (APA) or placebo combined with abiraterone acetate plus prednisone (AAP).

142 Background: In ACIS, APA + AAP improved radiographic progression-free survival in mCRPC vs AAP; difference in overall survival (OS) was not statistically significant. We report a prespecified analysis of androgen receptor (AR) or non-AR genomic/transcriptional aberrations, known to be associated with poor prognosis, and their associations with OS in patients (pts) with mCRPC. Methods: Circulating tumor (ct)DNA and aberrations in 17 PC-relevant genes were assessed using next-generation sequencing at baseline (BL; n = 197) and at end of study treatment (EOST; n = 140) (biomarker population). ctDNA was summarized qualitatively; genomic aberrations were normalized by ctDNA detection. AR splice variant version 7 (ARv7) was detected by quantitative RT-PCR. Cox proportional hazards model assessed association of OS with biomarkers in univariate/multivariate analyses overall and in pts receiving subsequent treatment (tx). Results: BL characteristics of biomarker and total study populations were similar. From BL to EOST: ctDNA detection did not differ (123/196 [63%] to 92/140 [66%], p=0.6); significant increases occurred in ARv7, AR mutations, and any AR aberration (Table). Prevalence of aberrations in PI3K and homologous recombination repair (HRR) pathways did not change from BL to EOST (40/123 [33%] to 34/92 [37%], p=0.5 and 18/123 [15%] to 14/92 [15%], p>0.9, respectively). Worse OS was associated with ctDNA detection or HRR pathway inactivation at BL (HR, 2.5 or 2.2; all p < 0.001) or presence of ctDNA, ARv7, AR amplification or inactivation of TP53, RB1, or RB1/TP35 pathway at EOST (2.2, p < 0.001; 2.1, p < 0.001; 2.6, p < 0.001; 1.5, p < 0.05; 1.7, p < 0.05; 2.1, p < 0.001, respectively) in univariate analyses. EOST ARv7, AR amplification, and inactivation of RB1, TP53, or RB1/TP53 pathway was associated with worse OS in pts receiving subsequent tx. Detection of ctDNA and RB1 inactivation at BL and RB1/TP53 pathway inactivation at EOST was strongly associated with worse OS (2.1, 3.3, 2.9, respectively, all p < 0.01) in multivariate analyses. Conclusions: In ACIS, AAP or APA + AAP tx was associated with increased AR mutations and ARv7 expression. Detection of ctDNA and select AR/non-AR aberrations may predict poor survival in mCRPC. These markers may be used to improve tx selection following confirmation of their predictive value. Clinical trial information: NCT02257736. [Table: see text]

Estimation of Overall Survival with Subsequent Treatment Effect by Applying Inverse Probability of Censoring Weighting in the LATITUDE Study

BackgroundIn the LATITUDE study (ClinicalTrials.gov, NCT01715285), compared with placebos, abiraterone acetate plus prednisone (AAP) with androgen deprivation therapy (ADT) provided significant overall survival (OS) benefit in high-risk metastatic castration-sensitive prostate cancer (mCSPC) patients. It is controversial whether survival benefits would remain if all patients in the placebo group subsequently received life-extending therapies. ObjectiveTo estimate treatment effect in the case of all patients in the placebo group receiving life-extending subsequent therapies. Design, setting, and participantsA post hoc analysis of LATITUDE final-analysis data was carried out (setting and participants have been reported previously). InterventionAAP or placebos plus ADT. Outcome measurements and statistical analysisWe applied the inverse probability of censoring weighting (IPCW) method to represent the situation in which all patients in the placebo group would have received life-extending subsequent therapies. The OS hazard ratio (HR) of AAP versus placebos and associated 95% confidence interval (CI) were estimated using a Cox proportional hazards model. Results and limitationsOf the 581 eligible patients in the placebo group, 237 (40.8%) did not receive life-extending subsequent therapies. From the unadjusted intention-to-treat analysis, the HR for OS for AAP versus placebos was 0.661 (95% CI 0.564–0.775). Using IPCW to adjust for patients in the placebo group without life-extending subsequent therapies, the HR was 0.732 (95% CI 0.604–0.887). A limitation is a lack of proof that the Cox proportional hazards model for the absence of life-extending subsequent therapy is correctly specified for the IPCW method. ConclusionsTreatment with AAP exerts OS benefit over placebos in high-risk mCSPC patients, regardless of whether life-extending subsequent therapy is given. Patient summaryIn a previous study, high-risk metastatic castration-sensitive prostate cancer patients who received abiraterone acetate plus prednisone (AAP) with androgen deprivation therapy generally survived longer than those given placebos. The benefit of adding AAP continues regardless of whether life-extending subsequent therapy is given.

Comparison of Abiraterone and Combined Androgen Blockade Therapy for High-Risk Metastatic Hormone-Sensitive Prostate Cancer: A Propensity Score-Matched Analysis.

This study aimed to compare the effects of abiraterone acetate plus prednisone (AAP) with androgen deprivation therapy (ADT) with those of combined androgen blockade (CAB) therapy in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study retrospectively identified 163 patients with high-risk mHSPC at Kindai University and affiliated hospitals between January 2014 and December 2020. Kaplan-Meier analysis was used to summarize progression-free survival (PFS) and overall survival (OS). Multivariate Cox proportional hazard modeling was used to identify the prognostic factors in the overall cohort. Propensity score matching was used to adjust the clinical characteristics, and log-rank test was applied to these propensity score–matched cohorts. Seventy-four patients who received AAP with ADT and 89 patients who received CAB were included in this study. The median follow-up duration was 27 months (range, 2–89 months). The median PFS and OS were not reached by the AAP+ADT group and 15 and 79 months, respectively, in the CAB group. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score and AAP+ADT were significant prognostic factors for PFS, whereas ECOG PS score, visceral metastasis, and AAP+ADT were significant prognostic factors for OS. The 2-year PFS was 76.1% in the AAP+ADT group and 38.6% in the CAB group (P < 0.0001), and the 2-year OS was 90.2% in the AAP+ADT group and 84.8% in the CAB group (P = 0.015). In conclusion, AAP+ADT had better PFS and OS than CAB in patients with high-risk mHSPC.

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.

PD34-06 SERUM TESTOSTERONE AS A PREDICTIVE BIOMARKER FOR PSA RESPONSE: RESULTS FROM A RANDOMISED TRIAL COMPARING ENZALUTAMIDE WITH ABIRATERONE ACETATE PLUS PREDNISONE

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III (PD34)1 Sep 2021PD34-06 SERUM TESTOSTERONE AS A PREDICTIVE BIOMARKER FOR PSA RESPONSE: RESULTS FROM A RANDOMISED TRIAL COMPARING ENZALUTAMIDE WITH ABIRATERONE ACETATE PLUS PREDNISONE Klara Kvorning Ternov, Jens Sønksen, Mikkel Fode, Henriette Lindberg, Rasmus Bisbjerg, Ganesh Palapattu, and Peter Busch Østergren Klara Kvorning TernovKlara Kvorning Ternov More articles by this author , Jens SønksenJens Sønksen More articles by this author , Mikkel FodeMikkel Fode More articles by this author , Henriette LindbergHenriette Lindberg More articles by this author , Rasmus BisbjergRasmus Bisbjerg More articles by this author , Ganesh PalapattuGanesh Palapattu More articles by this author , and Peter Busch ØstergrenPeter Busch Østergren More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002038.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Baseline serum testosterone has been suggested to be a predictive biomarker of patient important outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). Herein, we investigate the prostate-specific antigen (PSA) treatment response based on baseline testosterone levels in men treated first-line with enzalutamide (ENZ) or abiraterone acetate plus prednisone (AAP) for mCRPC. METHODS: We randomised (1:1) men to ENZ (160 mg/day) or AAP (1000 mg abiraterone acetate and 10 mg prednisone/day) groups, in this investigator-initiated phase IV trial. Eligible patients had progressive metastatic prostate cancer despite castrate levels of testosterone (<1.7nmol/L). The purpose of this trial was to compare side-effects between ENZ and AAP. In this exploratory analysis, patients were grouped according to baseline testosterone levels above the mean or less than or equal to the mean. PSA progression-free survival (PFS) was analysed with Kaplan-Meier and with univariate and multivariable (including treatment, testosterone and PSA) cox regression analyses. PSA response rates (≥50% reduction in PSA) were compared between testosterone groups with Chi-Square test for the entire cohort and treatment subgroups. Serum testosterone was measured by the gold standard assay liquid chromatography–tandem mass spectrometry. RESULTS: 166 patients (82 treated with ENZ and 84 with AAP) were included in the analyses. The mean baseline testosterone was 0.35nmol/L (10ng/dL). Median follow-up was 22.3 months. Men with baseline testosterone above the mean value had longer PSA PFS (16.6 vs. 9.9 months, hazard ratio 0.59, 95% confidence interval 0.41; 0.85, p=0.005). No interaction was found between treatment subgroups in PSA PFS (p=0.635). The PSA response rate was greater in those with higher testosterone compared with those with lower testosterone overall (91% vs 74%, p=0.007). This difference was only statistically significant in the AAP treatment subgroup (table 1). CONCLUSIONS: Baseline serum testosterone seems to be predictive of PSA response in men with mCRPC treated with ENZ or AAP and may be useful for risk stratification of men with mCRPC. Source of Funding: Herlev and Gentofte Hospital, Herlev, Denmark © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e584-e585 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Klara Kvorning Ternov More articles by this author Jens Sønksen More articles by this author Mikkel Fode More articles by this author Henriette Lindberg More articles by this author Rasmus Bisbjerg More articles by this author Ganesh Palapattu More articles by this author Peter Busch Østergren More articles by this author Expand All Advertisement Loading ...

588P Androgen changes after enzalutamide or abiraterone plus prednisone in men with castration-resistant prostate cancer (HEAT): Results from a randomised clinical trial

Enzalutamide (ENZ) and abiraterone acetate plus prednisone (AAP) are both androgen receptor targeting treatments for metastatic castration-resistant prostate cancer (mCRPC). AAP inhibits the androgen production, whereas ENZ blocks the androgen receptor signalling. Herein, we evaluate and compare treatment changes in serum androgens for ENZ and AAP.

626P Estimation of overall survival with subsequent treatment effect by applying inverse probability of censoring weighting in the LATITUDE study

In the LATITUDE study, abiraterone acetate plus prednisone (AAP) added to androgen deprivation therapy demonstrated significant overall survival (OS) benefit in patients with high-risk metastatic castration-sensitive prostate cancer (mCSPC), compared with placebo (PBO). Around 60% of patients received life-extending subsequent therapies (LEST) after PBO discontinuation. To our knowledge, this is the first analysis to estimate the real treatment effect adjusting for patients without LEST.

The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice

Simple SummaryCognitive side effects and fatigue after cancer treatment now constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next-generation therapies improving metastatic castration-resistant prostate cancer (mCRPC) patient survival, but also associated with neurological disturbances. We developed a behavioral 17 months-aged and castrated mouse model receiving AAP or ENZ for 5 days per week for six weeks. We establish that ENZ impacts locomotor and explorative behaviors, and strength capacity likely by preventing binding of central synthetized androgens to androgen receptors expressed by dopamine neurons of the Substantia Nigra and the Ventral Tegmentum. ENZ also reduces the cognitive score, associated with less neuronal activity in dorsal hippocampal areas. This demonstrates ENZ-specific consequences on motivation to exploration and cognition, being of particular importance for future management of elderly prostate cancer patients and their quality of life.Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients.

Quality of life in men with metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone: a systematic review and meta-analysis.

Enzalutamide and abiraterone acetate plus prednisone (AAP) have similar efficacy in metastatic castration-resistant prostate cancer (mCRPC), but different mechanisms of action. The aim was to compare patient-reported health-related quality of life (HRQoL) in men treated with enzalutamide vs AAP for mCRPC. We systematically reviewed the literature in June 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Patient-reported outcomes (PROs) until the last follow-up were summarised in a narrative synthesis. Short-term changes (12 weeks) in HRQoL, measured by the Functional Assessment of Cancer Therapy-Prostate total score (FACT-P), were compared between treatment groups and were analysed for enzalutamide and AAP in separate meta-analyses. Higher FACT-P scores indicate better HRQoL. Eight studies were included in the systematic review, four of which were randomised clinical trials (RCTs) eligible for the meta-analyses. The meta-analyses showed mean within-subject FACT-P changes from baseline to week 12 of -1.3 points (95% confidence interval [CI] -2.7; 0.1) for enzalutamide and 4.7 points (95% CI -0.1; 9.6) for AAP. One RCT and three non-randomised studies directly compared enzalutamide with AAP. The RCT showed better short-term HRQoL for AAP (6.8 FACT-P-points, 95% CI 1.7; 11.8) and better long-term HRQoL for AAP in men ≥75 years (7.35 FACT-P-points, 95% CI 2.59; 12.11). The non-randomised studies showed no difference in long-term HRQoL but had all a serious risk of bias. Limitations of the included studies include that the PRO in the included trials were inconsistently reported and that only one study defined the HRQoL measures in their published protocol. AAP seems to be associated with better short-term HRQoL than enzalutamide. This difference was not apparent at longer follow-up, but the long-term studies had serious risks of bias.

Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative neoadjuvant trial in high-risk localized prostate cancer.

Localized prostate cancers (PCs) may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of neoadjuvant indomethacin (Indo), which inhibits the steroidogenic enzyme AKR1C3, in addition to combinatorial anti-androgen blockade, in men with high-risk PC undergoing radical prostatectomy (RP). This was an open label, single-site, Phase II neoadjuvant trial in men with high to very-high-risk PC, as defined by NCCN criteria. Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo followed by RP. Primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included minimal residual disease (MRD) rate, defined as residual cancer burden (RCB) ≤ 0.25cm3 (tumor volume multiplied by tumor cellularity) and elucidation of molecular features of resistance. Twenty patients were evaluable for the primary endpoint. Baseline median prostate-specific antigen (PSA) was 10.1 ng/ml, 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had pCR and 6 (30%) had MRD. Therapy was well tolerated. Over a median follow-up of 23.8 months, 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse. There was no association between prostate hormone levels or HSD3B1 genotype with pathologic response. In men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy, although rates of MRD were higher. Ongoing follow-up is needed to validate clinical outcomes of men who achieve MRD.

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE)

PurposeTo assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC).MethodsBEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer.ResultsThirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib–apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation.ConclusionsThese results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib–AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC.Trial registration no.NCT02924766 (ClinicalTrials.gov).

Medication patterns of abiraterone acetate plus prednisone or enzalutamide and PSA progression in veterans with metastatic castration-resistant prostate cancer

Objectives To quantify the association between dose reductions of abiraterone acetate plus prednisone (AAP) or enzalutamide and prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC). Changes in medication-taking patterns of AAP or enzalutamide may arise due to clinical (e.g. toxicity) and non-clinical (e.g. patient compliance) reasons in men with mCRPC. However, it is unclear how this affects PSA progression. Methods Veterans Health Administration electronic health record database was used to identify Veterans diagnosed with prostate cancer who initiated AAP or enzalutamide (index) from April 2010 to December 2016. PSA progression was defined as the first rise in PSA of ≥2 ng/mL and ≥25% above nadir. The relative dose intensity (RDI) was defined as the ratio of the total dispensed dose over the last two months to the standard recommended dose and was updated monthly. Dose reduction was assessed using a threshold of RDI < 80%. Results The cohort included 6069 Veterans aged 74.6 years on average. Mean follow-up was 12.3 months. PSA progression occurred in 62.7% of patients. About 63.6% of AAP- and 67.2% of enzalutamide-treated patients had ≥1 occurrence of RDI <80%. RDI <80% was associated with an 8.8% higher risk of PSA progression (hazard ratio [HR] = 1.088; p = .019; 95% confidence interval [CI] [1.014; 1.166]). Conclusions Dose reduction was observed in most patients and was associated with significantly higher risk of PSA progression in men with mCRPC. These results suggest future efforts to minimize dose reductions for non-clinical reasons are warranted and that patient adherence should be encouraged to limit the risk of PSA progression.

Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naive metastatic castration-resistant prostate cancer (mCRPC).

9 Background: As mCRPC is driven by activated androgen receptors and elevated intratumoral androgens, androgen annihilation may require dual inhibition. APA and AA are approved prostate cancer therapies that have distinct receptor inhibition and ligand suppression actions, respectively. ACIS compared radiographic progression-free survival (rPFS) of APA + AAP vs PBO + AAP in chemo-naive mCRPC. Methods: mCRPC pts with ongoing androgen deprivation therapy (ADT) but no other life-prolonging treatment since diagnosis were randomized 1:1 to APA (240 mg po QD) + AA (1000 mg po QD) + P (5 mg po BID) or PBO + AAP (stratified by presence or absence of visceral metastases, Eastern Cooperative Oncology Group performance status 0 or 1, and geographic region). The primary end point was rPFS (investigator assessed; defined from randomization date to radiographic progression date or death). Secondary/other end points included prostate-specific antigen (PSA) response, overall survival (OS), safety, time to PSA progression, chronic opioid use, initiation of cytotoxic chemotherapy, and pain progression. Results: 982 pts were enrolled (Dec 2014 to Aug 2016). Median rPFS was extended 6 mos with APA + AAP (22.6 mos) vs AAP (16.6 mos) (HR 0.69 [95% CI 0.58-0.83]; p &lt; 0.0001) at the final analysis for rPFS, coinciding with the first interim analysis of OS (median follow-up time 25.7 mo). At final analysis, treatment with APA + AAP vs AAP showed a significantly higher rate of confirmed ≥ 50% PSA decline. Although not statistically significant, treatment with APA + AAP vs AAP showed a longer median OS. Time to PSA progression, chronic opioid use, initiation of cytotoxic chemotherapy, and pain progression did not differ statistically significantly between arms. The safety profile was consistent with prior drug experience, with no new safety concerns. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 63.3% (310/490) of APA + AAP–treated pts vs 56.2% (275/489) of AAP-treated pts, with more grade 3 (56.1%, 275/490 vs 45.6%, 223/489) and less grade 4 (7.1%, 35/490 vs 10.6%, 52/489) TEAEs, respectively. Results based on biomarker subpopulations and quality of life will be presented. Conclusions: The ACIS final analysis met the primary end point and demonstrated a 31% reduction in risk of radiographic progression or death in chemo-naive mCRPC pts treated with the combination of APA + AAP with ADT vs AAP with ADT. Funding: Janssen Research &amp; Development. Trial registration: NCT02257736. Clinical trial information: NCT02257736. [Table: see text]

AMPLITUDE: A study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC).

TPS176 Background: Clinical benefit has been observed with poly(ADP-ribose) polymerase (PARP) inhibition in patients with metastatic castration-resistant prostate cancer tumors that carry HRR gene defects. Niraparib is a highly selective and potent PARP inhibitor, with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. The objective of AMPLITUDE is to assess the efficacy and safety of niraparib/placebo added to AAP with androgen deprivation therapy (ADT) in a biomarker-selected population with mCSPC. Methods: AMPLITUDE (NCT04497844) is a phase 3, randomized, double-blind, placebo-controlled study with an expected enrollment of 788 patients at ~350 sites in ~30 countries. Clinical trial information: NCT04497844. [Table: see text]

Effects of abiraterone acetate plus prednisone on bone turnover markers in chemotherapy-naïve mCRPC patients after ADT failure: A prospective analysis of the italian real-world study ABITUDE

BackgroundBone remodeling is disrupted in metastatic disease, which affects > 70% of metastatic castration-resistant prostate cancer (mCRPC) patients. As a result, abnormal levels of specific bone turnover biomarkers (BTMs) are released. In this prospective ancillary analysis of the Italian real-world study ABITUDE, four markers were measured during abiraterone acetate plus prednisone (AAP) treatment in chemotherapy-naïve mCRPC men failing androgen-deprivation therapy. MethodsPatients were enrolled if a blood sample was obtained before the first administration of abiraterone (baseline); ad-hoc blood samples were withdrawn during routine tests after 3, 6, and 12 months. A centralized lab measured bone alkaline phosphatase (BALP, osteoblast activity marker), type-I collagen-C-telopeptide (CTX-1, bone resorption marker), parathyroid hormone (PTH) and vitamin D (vitD). At each time point, intra-patient variations vs baseline were compared by the signed-rank test (statistical significance: P-value < 0.05). ResultsOf 481 patients enrolled in ABITUDE, 186 (median age: 76 [range: 53–93] years) met the substudy criteria: 74.7% had bone metastases, 11.8% were on bone-targeted therapies (BTT) and 14.0% on vitD supplementation. BALP decreased significantly at month 6 (P = 0.0010) and 12 (P < 0.0001) and CTX-1 at month 6 (P = 0.0028); PTH increased at month 3 (P < 0.0001); no significant difference in vitD levels was observed. Similar findings were observed in BTT-untreated patients. The reduction in BALP and CTX-1 levels was more pronounced in patients with than without bone metastases; in the latter group, no significant variation in BALP and CTX-1 levels was observed. ConclusionsAAP seems to exert an effect on the microenvironment of metastatic but not of normal bone, which likely contributes to its antitumoral activity.

Combination of Radiation Therapy and Short-Term Androgen Blockade With Abiraterone Acetate Plus Prednisone for Men With High- and Intermediate-Risk Localized Prostate Cancer

Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control. This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life. We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA < 20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months. The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.

651P Impact of abiraterone acetate plus prednisone (AAP) in patients with castration-sensitive prostate cancer (mCSPC) and visceral metastases: Subgroup analyses of the LATITUDE study

651P Impact of abiraterone acetate plus prednisone (AAP) in patients with castration-sensitive prostate cancer (mCSPC) and visceral metastases: Subgroup analyses of the LATITUDE study

Cost-Effectiveness of Metastasis-Directed Therapy in Oligorecurrent Hormone-Sensitive Prostate Cancer

Oligorecurrent prostate cancer has historically been treated with indefinite androgen deprivation therapy (ADT), although many patients and providers opt to defer this treatment at the time of recurrence given quality-of-life and/or comorbidity considerations. Recently, metastasis-directed therapy (MDT) has emerged as a potential intermediary between surveillance and immediate continuous ADT. Simultaneously, advanced systemic therapy in addition to ADT has also been shown to improve survival in metastatic hormone-sensitive disease. This study aimed to compare the cost-effectiveness of treating oligorecurrent patients with upfront MDT before standard-of-care systemic therapy. A Markov-based cost-effectiveness analysis was constructed comparing 3 strategies: (1) upfront MDT → salvage abiraterone acetate plus prednisone (AAP) + ADT → salvage docetaxel + ADT; (2) upfront AAP + ADT → salvage docetaxel + ADT; and (3) upfront docetaxel + ADT → salvage AAP + ADT. Transition probabilities and utilities were derived from the literature. Using a 10-year time horizon and willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY), net monetary benefit values were subsequently calculated for each treatment strategy. At 10 years, the base case revealed a total cost of $141,148, $166,807, and $136,154 with QALYs of 4.63, 4.89, and 4.00, respectively, reflecting a net monetary benefit of $322,240, $322,018, and $263,407 for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. In the probabilistic sensitivity analysis using a Monte Carlo simulation (1,000,000 simulations), upfront MDT was the cost-effective strategy in 53.6% of simulations. The probabilistic sensitivity analysis revealed 95% confidence intervals for cost ($75,914-$179,862, $124,431-$223,892, and $103,298-$180,617) and utility in QALYs (3.85-6.12, 3.91-5.86, and 3.02-5.22) for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. At 10 years, upfront MDT followed by salvage AAP + ADT, is comparably cost-effective compared with upfront standard-of-care systemic therapy and may be considered a viable treatment strategy, especially in patients wishing to defer systemic therapy for quality-of-life or comorbidity concerns. Additional studies are needed to determine whether MDT causes a sustained meaningful delay in disease natural history and whether any benefit exists in combining MDT with upfront advanced systemic therapy.

A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (MAGNITUDE).

TPS5588 Background: Preclinical data suggest synergistic antitumor activity when the PARP inhibitor (PARPi) niraparib is combined with the androgen pathway inhibitor abiraterone acetate1. The addition of a PARPi to abiraterone acetate plus prednisone (AAP) showed improved radiographic progression-free survival (rPFS) vs AAP alone in patients with mCRPC regardless of DNA repair gene defect (DRD) status2. Interim results from a phase I study support safety and tolerability of niraparib 200 mg combined with AAP in patients with mCRPC3. The objective of this Phase III study is to compare the efficacy and safety of niraparib plus AAP versus AAP with placebo as first-line therapy for mCRPC. Methods: This ongoing multicenter MAGNITUDE study (NCT03748641) will open in approximately 300 sites across 28 countries and will enroll patients with mCRPC who have not received treatment in the metastatic castrate resistant setting other than ongoing androgen deprivation therapy [ADT] and ≤4 months of AAP. DRD status will be determined by plasma and tissue assays. The cohort with DRD (n=400) and the cohort without DRD (n=600) will each be randomized 1:1 to niraparib + AAP or placebo + AAP. The first patient was consented in February 2019 and enrollment is ongoing. The primary objective of the study is to compare radiographic progression-free survival (rPFS) as assessed by blinded independent central radiology review in each cohort and treatment group. To test superiority of the combination vs AAP, sample sizes were estimated to provide 92% power to detect HR≤0.65 rPFS in the cohort with DRD and 94% power to detect HR≤0.67 in rPFS in the cohort without DRD, both at a 2-tailed level of significance of 0.05. The secondary objectives are time to symptomatic progression, time to cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic profiles will be evaluated. 1Rajendra N, et al. Cancer Res 2019;79(13 Suppl):Abstract nr 2134. 2Clarke N, et al. Lancet Oncol. 2018;(7):975-986. 3Saad, et al. Ann Oncol, 2018;29 (suppl 8), mdy284.043, https://doi.org/10.1093/annonc/mdy284.043 ) Clinical trial information: NCT03748641 .

Quality of life (QOL) for the treatment sequence of abiraterone acetate plus prednisone (AAP) followed by enzalutamide (ENZ) versus the opposite sequence for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized clinical trial.

5578 Background: A randomized cross-over phase II trial (Lancet Oncol 20(12):1730, 2019) showed the sequence of AAP followed by ENZ is associated with a better time to PSA progression compared with the opposite sequence and superior 2nd line activity of ENZ. It is unknown whether one treatment sequence is associated with better QOL than the other. Methods: 202 Patients were randomized (1:1) to receive either AAP followed by ENZ at PSA progression (arm A) or the opposite sequence of ENZ followed by AAP (arm B). FACT-P questionnaires were completed at baseline, cross-over and every 4 weeks on treatment. Time to QOL deterioration (TTQOLD) for the treatment sequence was determined from start of 1st line treatment to first questionnaire with a clinically meaningful decrease from baseline and compared between arms using the log-rank test. TTQOLD was also determined for 1st line and 2nd line separately. The proportion of patients with QOL deterioration for total FACT-P score and FACT-P subscores from baseline to week 12 of 1st and 2nd line treatment was compared between arms using X2 test. Results: Median follow-up for 1st and 2nd line and whole sequence were 9.3, 6.6 and 22.0 months (mos) respectively and questionnaire completion rate was 81%. TTQOLD for total FACT-P score for the whole sequence for arm A vs B was 10.5 mo (95% CI 5.0-15.5) vs 10.8 mo (5.5-13.1), p = 0.74. For 1st-line AAP vs ENZ, median TTQOLD was 15.5 mo (5.5-21.2) vs 11.0 (5.5-13.3) respectively (p = 0.23). For 2nd line ENZ vs ABI, median TTQOLD was 3.7 mo (2.0-5.4) vs 5.8 (2.8-12.1), p = 0.13. There was a higher rate of deterioration in physical well-being (PWB) for 1st line ENZ (arm B) and 2nd line ENZ (arm A) (Table). Conclusions: There was no difference in TTQOLD between the two treatment sequences of AAP and ENZ. Although treatment with second line ENZ has been associated with greater anti-cancer effects, ENZ was associated worse PWB QOL scores. Clinical trial information: NCT02125357 . [Table: see text]