Abiraterone In Patients Research Articles

Real-World Clinical Outcomes of Low Dose versus Standard Dose Abiraterone in Patients with Metastatic Castration-Resistant Prostate Cancer: A Prospective Pragmatic Study

Introduction: Abiraterone is a standard treatment for metastatic castration-resistant prostate cancer (mCRPC). Food intake has shown significant effect on its pharmacokinetics. The aim of this study was to evaluate the efficacy and safety of standard dose abiraterone under fasting conditions versus low dose abiraterone with a low-fat meal in patients with mCRPC. Methods: In this prospective real world study 32 patients with mCRPC were treated in two groups of 16 cases by routine clinical practice of their treating physician with low-dose abiraterone (250 mg with a low fat breakfast) or standard-dose abiraterone (1000 mg in fasting state). The changes in serum prostate specific antigen (PSA) level and PSA response rate (≥50% reduction after 12 weeks) were the primary end points. Results: The median changes of serum PSA before and after treatment, as well as the PSA nadir were not significantly different between the two groups (P = 0.128 and P = 0.051, respectively). Despite a trend toward higher PSA response rate in the low-dose group, the difference was not statistically significant (75.0% vs. 62.5%; P = 0.704). Median serologic progression free survival (PFS) was significantly higher in the low-dose group (15 vs. 8 months; Log-rank P = 0.031). There was a trend toward lower adverse events in the low-dose group, but this difference was not statistically significant (37.5% vs. 62.5%; P = 0.289). Conclusion: Low-dose abiraterone seems to be comparable to standard-dose abiraterone in mCRPC with 75% lower financial cost; however, this conclusion needs to be proved by further well designed and large scale studies.

Comparison of infection risk between enzalutamide and abiraterone in patients with prostate cancer.

Enzalutamide and abiraterone may differ in their immunomodulatory effects, and the prednisone coadministered with abiraterone can be immunosuppressive. This study aimed to compare the risk of different types of infection in patients with prostate cancer receiving enzalutamide or abiraterone in combination with androgen deprivation therapy. Patients with prostate cancer receiving enzalutamide or abiraterone in addition to androgen deprivation therapy in Hong Kong between December 1999 to March 2021 were identified in this retrospective cohort study and followed up until September 2021, death, or crossover. Outcomes, including any sepsis, pneumonia, urinary tract infection, cellulitis or skin abscess, central nervous system infections, and tuberculosis, were analyzed as both time-to-event outcomes (multivariable Fine-Gray regression, with mortality considered a competing event) and recurrent-event outcomes (multivariable negative binomial regression). Altogether, 1582 patients were analyzed (923 abiraterone users; 659 enzalutamide users) with a median follow-up of 10.6 months (interquartile range: 5.3-19.9 months). Compared to abiraterone users, enzalutamide users had lower cumulative incidences of sepsis (adjusted subhazard ratio [SHR] 0.70 [0.53-0.93], p=.014), pneumonia (adjusted SHR 0.76 [0.59-0.99], p=.040), and cellulitis or skin abscess (adjusted SHR 0.55 [0.39-0.79], p=.001), but not urinary tract infection (adjusted SHR 0.91 [0.62-1.35], p=.643). Associations between exposure and central nervous system infections and tuberculosis were not assessed because of low event rates. Analyzing the outcomes as recurrent events gave similar results. Enzalutamide use may be associated with a lower risk of urinary tract infection in patients with diabetes mellitus. Compared to abiraterone users, enzalutamide users have significantly lower risks of sepsis, pneumonia, cellulitis, or skin abscess.

CYCLONE 2: A phase 3 study of abemaciclib with abiraterone in patients with metastatic castration-resistant prostate cancer.

5001 Background: Oncogenic addiction to androgen receptor (AR) signaling drives mCRPC progression, highlighting the unmet need for novel treatment strategies to maximize AR-directed therapy. Preclinical evidence suggests a key role for CDK4/6 in sustained AR signaling, uncontrolled proliferation, and hormonal resistance in prostate cancer. Abemaciclib (ABEMA) is a potent CDK4/6 oral inhibitor that significantly augments the efficacy of endocrine therapy in hormonally driven (ER+) high-risk early-stage and metastatic breast cancer. ABEMA also showed single-agent activity in heavily pretreated mCRPC. Here, we report the primary results of CYCLONE 2, a Phase 3 study of ABEMA plus abiraterone (ABI) in pts with 1L mCRPC. Methods: CYCLONE 2 was a seamless Phase 2/3 adaptive trial with a dose-finding safety lead-in. Randomization to the ABEMA or placebo (PBO) plus ABI and predniso(lo)ne was stratified by prior docetaxel receipt for mHSPC, measurable disease, and radiographic progression at study entry. Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3. The study was powered at ~90%, assuming a HR of 0.55 for rPFS, at a cumulative 2-sided alpha level of 0.05. Results: Between Nov 2018 and Jul 2022, 393 pts were randomized. Baseline characteristics were balanced across arms. Primary endpoint of rPFS was not met (HR 0.829; 95% CI, 0.619–1.111; p=0.2123), medians were 21.96 months for the ABEMA plus ABI group vs 20.28 months for the PBO plus ABI group. rPFS by blinded independent central review was consistent with investigator assessment (HR 0.842; 95% CI, 0.611–1.160). OS was a gated secondary endpoint and not inferentially tested (HR 0.927; 95% CI, 0.669–1.285; 38.9% maturity). Other secondary endpoints included time to PSA progression (HR 0.637; 95% CI, 0.474–0.856), time to symptomatic progression (HR 0.768; 95% CI, 0.522–1.131), and time to worst pain progression (HR 0.935; 95% CI 0.665–1.314). The most common grade ≥3 adverse events (AEs) reported in the ABEMA plus ABI group were anemia (13.6% vs 4.3% in the PBO plus ABI group), neutropenia (12.6% vs 0.5%) and ALT increased (8.7% vs 6.5%). Discontinuations of all study treatments due to AEs were 13.1% vs 4.3% in ABEMA plus ABI vs PBO plus ABI groups, while discontinuations of ABEMA or PBO alone due to AEs were 5.8% vs 1.6%, respectively. Conclusions: In patients with mCRPC, adding abemaciclib to abiraterone did not significantly increase rPFS. While no OS detriment was observed, secondary endpoints were not meaningfully improved. Overall, the combination was well tolerated, and safety was consistent with the known profiles of the individual medicines. Clinical trial information: NCT03706365 Clinical trial information: NCT03706365 .

Tolerability of Olaparib Combined with Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer: Further Results from the Phase 3 PROpel Trial

BackgroundThe PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. ObjectiveWe report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. Design, setting, and participantsA randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018–January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. InterventionOlaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). Outcome measurements and statistical analysisThe data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. Results and limitationsThe most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). ConclusionsOlaparib plus abiraterone has a manageable and predictable safety profile. Patient summaryThe PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.

Predictive Factors of Abiraterone Response in Patients With High-Risk Metastatic Hormone-Sensitive Prostate Cancer

Purpose: This study aimed to identify predictive factors for the response to abiraterone in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC).Materials and Methods: This study analyzed the clinical characteristics of 167 patients with high-risk mHSPC who received abiraterone. Univariate and multivariable Cox proportional hazard regression analyses were conducted to identify predictive factors for castration-resistant prostate cancer (CRPC)-free survival and cancer-specific survival.Results: The mean age at presentation was 71.62±8.12 years. The prostate-specific antigen level was 218 ng/mL (interquartile range, 70–654 ng/mL). Of the 167 patients, 118 (72%) had a biopsy Gleason grade of 5, 43 patients (28.7%) had CRPC, and 30 patients (18.0%) died after a mean follow-up period of 13.5 months. In the multivariable Cox proportional hazard regression analyses for CRPC-free survival, a Gleason grade of 5 (hazard ratio [HR], 2.888; 95% confidence interval [CI], 1.133–7.361; p=0.026) and bone lesions ≥10 (HR, 4.194; 95% CI, 1.760–9.997; p=0.001) were significantly associated with CRPC-free survival. In the multivariable Cox proportional hazard regression analyses for cancer-specific survival, bone lesions ≥10 (HR, 3.185; 95% CI, 1.215–8.348; p=0.001) was significantly associated with cancer-specific survival.Conclusions: Patients with bone lesions ≥10 and Gleason grade of 5 are at higher risk of developing CRPC, and bone lesions ≥10 is at higher risk of cancer-specific survival in high-risk mHSPC treated with abiraterone.

Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial

PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis. This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0-1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system-interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting. Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1-40·3) for olaparib plus abiraterone and 36·5 months (33·8-40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4-not reached) with olaparib plus abiraterone and 34·7 months (31·0-39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67-1·00; p=0·054). The most common grade 3-4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related. Overall survival was not significantly different between treatment groups at this final prespecified analysis. Supported by AstraZeneca and Merck Sharp & Dohme.

Enzalutamide vs abiraterone in patients with prostate cancer with and without type 2 diabetes mellitus.

5066 Background: Estimations are that 8-18% of newly diagnosed cancer patients have Type 2 Diabetes Mellitus (T2DM). Current guidelines offer no clarification on the choice of therapy for prostate cancer (PCa) patients with T2DM. Since the comorbid PCa—T2DM population is increasing and these patients face unique challenges from adverse events requiring acute care utilization (ACU) it is important to ascertain which medication poses less of a threat of adverse events. The objective of this study was to describe the SEER-Medicare T2DM-PCa population in terms of those with and without complications and determine if T2DM influences ACU and PCa medication choice. Methods: We identified men with primary PCa treated with abiraterone (ABI, 2011) or enzalutamide (ENZ, 2012) with comorbid T2DM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (1999-2019). Patients with a missing date of diagnosis, those diagnosed at death, having HMO or no continuous A and B coverage 12 months before diagnosis and 6 months continuous part D coverage before starting treatment as well as 6 months following treatment or until death were excluded. T2DM was identified using ICD-9 and ICD-10 codes. ACU was calculated utilizing the CMS Research Data Assistance Center definition focusing on emergency room visits resulting in in-patent hospitalization during the 6 months following treatment initiation. Differences in emergency room in-patient visits were evaluated using negative binomial models adjusted for age, race, SEER region, marital status, state-buyin, education, income, and modified Charlson Comorbidity Index (excluding T2DM). Results: The sample of 11,163 men included 61.8% treated with ABI and 38.2% with ENZ. We identified 3,044 (27.3%) men with T2DM, of which, 59.1% were treated with ABI and 40.8% with ENZ. Compared to those without T2DM those with T2DM had more ACU, regardless of medication, with a higher rate in the ABI than ENZ group, see table. Among diabetics, those with complications related to T2DM compared to those without also experienced a higher rate of ACU. The rate of ACU was 43% higher among those treated with ABI compared to ENZ (IRR 1.43; 95% CI 1.28, 1.61). Overall mortality (15.7% vs 10.1%, p<0.01) and PCa-specific mortality (8.2% vs 5.3%, p<0.01) were worse in those with T2DM treated with ABI compared to ENZ. Conclusions: Outcomes for PCA patients with T2DM are worse than for those without. ACU is higher in men treated with ABI compared to ENZ regardless of T2DM status. Given the worse outcomes for comorbid T2DM patients, further study to evaluate comorbidity management in this population is warranted. [Table: see text]

CABIOS trial: A phase Ib study of cabozantinib and nivolumab in combination with abiraterone in patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC).

5084 Background: Androgen deprivation therapy (ADT) combined with novel hormonal agents +/- docetaxel is a standard of care treatment for mHSPC. The combination of tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) is FDA approved in renal cell carcinoma, and shows promising efficacy in preclinical models of prostate cancer by favorably altering the tumor immune microenvironment. There are currently ongoing trials of TKI + ICB in metastatic castration resistant prostate cancer. Here we present interim safety results from an ongoing phase Ib single-arm trial of cabozantinib + nivolumab + abiraterone/prednisone (cabo, nivo, abi/pred) in pts with newly diagnosed mHSPC (NCT04477512). Methods: Eligible pts had de-novo or recurrent mHSPC with up to 12 weeks ADT prior to enrollment, ECOG 0-1, and adequate organ function. Prior abi and docetaxel were excluded. Pts received cabo 20 mg or 40 mg daily (3+3 dose escalation in 2 cohorts) combined with nivo 480mg IV q4 weeks, and abi/pred 1,000mg/5mg daily until progression or unacceptable toxicity. The primary endpoint is safety and tolerability. Secondary endpoints include overall response rate (ORR) by RECIST 1.1, overall survival (OS), progression free survival (PFS), and PSA response. Exploratory analyses include CyTOF of peripheral blood and serum cytokine ELISA. Results: As of 19DEC2022, 17 pts were enrolled, 3 at 20mg and 14 at 40mg cabo with no dose-limiting toxicity (DLTs) observed. Median age was 65 yrs, 4/17 pts are Black, 11 had de-novo and 6 recurrent disease, with median baseline PSA 78ng/mL. Most had bone (n=16), lymph node (6), or lung (1) mets, and 11 (64.7%) had high-volume disease. With median follow-up 12.8 months, 9 pts (53%) remain on study. 1 withdrew, 3 discontinued due to disease progression (with 1 death), and 4 stopped due to toxicity. Grade ≥ 3 adverse events (AEs) include encephalitis (n=1, grade 4 likely nivo-related after 1yr on therapy), diarrhea (n=2), elevated AST/ALT (n=4), wound infection/dehiscence, adrenal insufficiency, hypertension, elevated lipase, and proteinuria (grade 3, n=1 each). No other AEs were reported outside the current safety labels for the study agents. Of 15 response evaluable pts, 7 had RECIST-measurable lesions; 4 had partial response and 3 had stable disease as best response at data cutoff. 9/14 (64.3%) evaluable had PSA <0.2ng/mL at 7 months. Immune correlative studies are ongoing. Conclusions: Here we present the initial safety and preliminary efficacy results of the first trial of cabo + nivo in mHSPC patients receiving SOC ADT + abi. To date, the combination has a safety profile consistent with known AEs for these agents, no DLTs, and evidence of clinical benefit. Further follow up will be required to fully assess clinical safety, efficacy and immune responses. Future, larger studies could compare this combination to SOC ADT + abi. Clinical trial information: NCT04477512 .

Effect of Prior Local Therapy on Response to First-line Androgen Receptor Axis Targeted Therapy in Metastatic Castrate-resistant Prostate Cancer: A Secondary Analysis of the COU-AA-302 Trial

BackgroundMen with localized prostate cancer are often treated with local therapy (LT). However, a proportion of these patients will eventually develop recurrence and progression requiring systemic therapy. Whether primary LT affects the response to this subsequent systemic treatment is unclear. ObjectiveWe investigated whether the receipt of prior prostate-directed LT influenced the response to first-line systemic therapy and survival in docetaxel-naïve metastatic castrate-resistant prostate cancer (mCRPC) patients. Design, setting, and participantsThis is an exploratory analysis of the COU-AA-302 trial, a multicentric double-blinded phase 3 randomized controlled trial in which mCRPC patients with no to mild symptoms were randomized to receive abiraterone plus prednisone or placebo plus prednisone. Outcome measurements and statistical analysisWe compared the time-varying effects of first-line abiraterone in patients with and without prior LT using a Cox proportional hazard model. The cut points were chosen using grid search, and were 6 and 36 mo for radiographic progression-free survival (rPFS) and overall survival (OS), respectively. We also investigated whether there was any difference in treatment effect on score change (relative to baseline) in various patient-reported outcomes (measured by Functional Assessment of Cancer Therapy—Prostate [FACT-P]) over time depending on the receipt of prior LT. The adjusted association of prior LT with survival was determined using weighted Cox regression models. Results and limitationsAmong 1053 eligible patients, 64% (n = 669) received prior LT. We did not find any statistically significant heterogeneity of time-dependent treatment effect from abiraterone on rPFS in patients with (hazard ratio [HR]: 0.36 [95% confidence interval: 0.27–0.49] at ≤6 mo; 0.64 [0.49–0.83] at >6 mo) or without (HR: 0.37 [0.26–0.55] at ≤6 mo; 0.72 [0.50–1.03] at >6 mo) prior LT. Similarly, there was no significant heterogeneity in time-dependent treatment effect on OS with (HR: 0.88 [0.71–1.10] at ≤36 mo; 0.76 [0.52–1.11] at >36 mo) or without (0.78 [0.60–1.01] at ≤36 mo; 0.55 [0.30–0.99] at >36 mo) prior LT. We did not find sufficient evidence of a difference in treatment effect from abiraterone on score change over time in prostate cancer subscale (interaction p = 0.4), trial outcome index (interaction p = 0.8), and FACT-P total score (interaction p = 0.6) depending on the receipt of prior LT. Receipt of prior LT was associated with a significant improvement in OS (average HR: 0.72 [0.59–0.89]). ConclusionsThis study demonstrates that the efficacy of first-line abiraterone and prednisone in docetaxel-naïve mCRPC do not vary significantly based on the receipt of prior prostate-directed LT. Further studies are needed to explore the plausible mechanisms of the association of prior LT with superior OS. Patient summaryThis secondary analysis of the COU-AA-302 trial suggests that survival benefits and temporal changes in quality of life with first-line abiraterone in docetaxel-naïve mCRPC do not differ significantly among patients who received versus those who did not receive prior prostate-directed local therapy.

Phase 1b study of bavdegalutamide, an androgen receptor PROTACdegrader, combined with abiraterone in patients with metastatic prostate cancer.

TPS5106 Background: Bavdegalutamide (ARV-110) is a novel, oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that targets wild-type androgen receptor (AR) and clinically relevant mutants. Bavdegalutamide demonstrated tumor growth inhibition in multiple xenograft models (eg, AR gene amplification, AR mutation, enzalutamide resistance, and enzalutamide insensitivity). In a phase 1/2 study (NCT03888612), bavdegalutamide showed clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received 1–2 prior novel hormonal agents (eg, abiraterone and/or enzalutamide), including heavily pretreated patients. Abiraterone is approved, in combination with a corticosteroid, to treat patients with mCRPC or with high-risk castration-sensitive prostate cancer (CSPC). Up to a third of patients treated with abiraterone develop primary resistance to this drug and nearly all patients experience disease progression. Here we describe a phase 1b study that will evaluate the combination of bavdegalutamide with abiraterone at the initiation of progression on abiraterone (prostate-specific antigen [PSA] progression without radiographic progression) to test if the addition of bavdegalutamide will overcome resistance to abiraterone and re-establish the AR pathway blockade in patients with prostate cancer. Methods: Eligible patients are men ≥18 years of age with histologically, pathologically, or cytologically confirmed adenocarcinoma of the prostate and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients must be receiving ongoing treatment with stable doses of abiraterone and a concomitant corticosteroid for mCRPC or CSPC and have PSA progression ≥16 weeks after initiation of abiraterone, ≥2 rising PSA values measured ≥1 week apart, and no radiographic evidence of disease progression while receiving abiraterone. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analogue or inhibitor or orchiectomy is required. Prior treatment with enzalutamide, apalutamide, darolutamide, or experimental AR-directed therapies is not permitted. Bavdegalutamide, abiraterone, and a corticosteroid will be administered daily in 28-day cycles. Primary objectives are to evaluate the safety and tolerability of bavdegalutamide plus abiraterone and determine the recommended phase 2 dose and schedule of this combination (based on the incidence of first-cycle dose-limiting toxicities and the frequency and severity of adverse events and laboratory abnormalities). Clinical trial information: NCT05177042.

Olaparib combined with abiraterone versus olaparib alone for patients with DNA-repair deficient metastatic castration-resistant prostate cancer after progressing on abiraterone: A multicenter, real-world study.

e17021 Background: Accumulated evidence reports that olaparib has antitumor activity for patients with DNA-repair deficient (DRD) metastatic castration-resistant prostate cancer (mCRPC). Olaparib monotherapy also has significantly longer survival outcomes in patients with DRD mCRPC after progressing on a novel hormonal therapy (NHT) than physician’s choice of another subsequent NHT. In addition, clinical trials indicate that olaparib combined with abiraterone is more effective than abiraterone alone for mCRPC patients irrespective of DRD status. However, the efficacy of olaparib combined with abiraterone in patients with DRD mCRPC after progressing on abiraterone has not been studied. Therefore, we conducted a multicenter, real-world study to compare olaparib combined with abiraterone versus olaparib alone for patients with DRD mCRPC. Methods: A total of 89 mCRPC patients from three Chinese hospitals were retrospectively studied between October 2017 and November 2021. All the patients had disease with progression after abiraterone and with DRD status by a 50-gene panel targeted next-generation sequencing (NGS), including pathogenic, suspected pathogenic, or variants of unknown significance (VUS) in the DNA damage repair (DDR) genes. 35 patients received olaparib combined with abiraterone and 54 olaparib alone. The primary end point included progression-free survival (PFS) and overall survival (OS) which were calculated using Kaplan-Meier methods, and compared using Cox proportional hazards model. The safety was also evaluated. Results: There was no difference in the basline characteristics between the two groups. The median follow-up time was 9 months (range 1-48 months). The median PFS and OS were significantly higher in patients receiving olaparib combined with abiraterone than in those receiving olaparib alone respectively (PFS: 6 vs. 3 months; OS: 24 vs. 12 months, both p < 0.01). Moreover, olaparib combined with abiraterone had a better adjusted hazard ratio of 0.385 (95% CI 0.230-0.643, p < 0.001) and 0.359 (95% CI 0.175-0.737, p = 0.005) as compared to monotherapy in PFS and OS respectively. Some drug-related adverse events, such as nausea and anemia, were reported, and the serious adverse events were rare, which were similar to those previously reported. Conclusions: Olaparib combined with abiraterone had better PFS and OS compared with olaparib alone in Patients with DRD mCRPC after progressing on abiraterone, suggesting a potential synergistic effect of olaparib with abiraterone in clinical settings. Both the combination therapy and monotherapy were relatively well tolerated in the mCRPC patients and the adverse events were within acceptable limits. The results need to be further confirmed by a large-scale prospective randomized controlled trial.

Real-world survival outcomes of adding docetaxel or abiraterone in patients with high-volume metastatic castration-sensitive prostate cancer: historically controlled, propensity score matched comparison with androgen deprivation therapy.

This study investigated the impact of treatment intensification with upfront docetaxel (DOC) or abiraterone (ABI) plus prednisolone on survival outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) by comparing it with androgen deprivation therapy (ADT) monotherapy or combined androgen blockade (CAB) using propensity score matching (PSM). Outcomes from 278 CHAARTED high-volume patients receiving upfront DOC (92 patients) or upfront ABI (186 patients) were compared to those from 354 patients receiving ADT or CAB. PSM was conducted to assess castration-resistant prostate cancer-free survival (CRPCFS) and overall survival (OS). After PSM, patient distributions between the three groups were well balanced. After 1:1 PSM, patients receiving upfront ABI had significantly better CRPCFS than those receiving ADT/CAB or upfront DOC [hazard ratio (HR) 0.39; 95% CI 0.27-0.56 vs. HR 0.50; 95% CI 0.30-0.82, respectively]. No significant difference in CRPCFS was observed between the upfront DOC and ADT/CAB groups (HR 0.75; 95% CI 0.50-1.12). Patients receiving upfront DOC and upfront ABI had significantly better OS than those receiving ADT/CAB (HR 0.54; 95% CI 0.0.30-0.98 vs. HR 0.49; 95% CI 0.29-0.84, respectively). However, no significant difference in OS was observed between upfront ABI and upfront DOC (hazard ratio 0.84; 95% CI 0.34-2.06). The comparison of real-world retrospective cohorts showed that treatment intensification with upfront DOC or upfront ABI promoted better OS compared to ADT alone or CAB in patients with high-volume mCSPC after PSM. However, no difference in OS was observed between upfront DOC and upfront ABI.

Novel hormonal agents for metastatic Castration-Resistant Prostate Cancer: comparing outcomes. A single-center retrospective study.

Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancerrelated deaths amongst men worldwide. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. To evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastatic prostate cancer in an academic center. We retrospectively reviewed patients treated for castration-resistant prostate cancer with either abiraterone or enzulatamide between January 1, 2016 and December 31, 2019. The primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. Enzalutamide had a higher biochemical response rate than abiraterone in patients with mCRPC (77.1% vs 58.1%, p = 0.016). Achieving a biochemical response was associated with a lower risk of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038). Enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical significance. Well-designed prospective studies are needed to elucidate the comparative efficacies of these agents.

Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial

The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss. We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238. Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo-abiraterone group and 547 (50%) to the ipatasertib-abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0-33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo-abiraterone group and 260 in the ipatasertib-abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9-17·0) in the placebo-abiraterone group and 18·5 months (16·3-22·1) in the ipatasertib-abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61-0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6-19·1) in the placebo-abiraterone group and 19·2 months (16·5-22·3) in the ipatasertib-abiraterone group (HR 0·84 [95% CI 0·71-0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo-abiraterone group and in 386 (70%) of 551 patients in the ipatasertib-abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo-abiraterone group and 116 (21%) in the ipatasertib-abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo-abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb-abiraterone group. Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis. F Hoffmann-La Roche and Genentech.

Survival outcomes in patients with chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone acetate

ObjectiveEvaluation of the comparative effectiveness of enzalutamide and abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) is limited to meta-analyses of randomized trials that exclude patients with significant comorbidities. We evaluated overall survival (OS) in patients with chemotherapy-naive mCRPC treated with enzalutamide or abiraterone acetate (abiraterone) in a real-world single payer setting.MethodsA retrospective analysis (4/1/2014–3/31/2018) of the Veterans Health Administration (VHA) database was conducted. Patients with mCRPC had ≥1 pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following disease progression on surgical/medical castration, without chemotherapy <12 months prior to index date. Patients had continuous VHA enrollment for ≥12 months pre-index date and were followed until death, disenrollment, or end of study. Kaplan–Meier analysis and multivariable Cox proportional hazards regression models examined the OS treatment effect.ResultsPatients with chemotherapy-naive mCRPC (N = 3174; enzalutamide, n = 1229; abiraterone, n = 1945) had mean ages of 74 and 73 years, respectively. Median follow-up was 18.27 and 19.07 months with enzalutamide and abiraterone, respectively. Enzalutamide-treated patients had longer median treatment duration than abiraterone-treated patients (9.93 vs 8.47 months, respectively, p = 0.0008). After baseline comorbidity adjustment, enzalutamide-treated patients had a 16% reduced risk of death (hazard ratio [HR] = 0.84; 95% CI, 0.76–0.94; p = 0.0012). For patients who remained on first line-therapy only, enzalutamide-treated patients had improved OS versus abiraterone-treated patients (HR = 0.71; 95% CI, 0.62–0.82). Enzalutamide-treated patients who crossed over to abiraterone had a comparable risk of death versus abiraterone-treated patients who crossed over to enzalutamide (HR = 1.10; 95% CI, 0.89–1.35). These results were confirmed by sensitivity analysis, which considered prognostic variables.ConclusionsRetrospective analysis of the VHA database indicated that chemotherapy-naive patients with mCRPC initiating therapy with enzalutamide had improved survival versus abiraterone.

A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281).

TPS178 Background: In metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone combined with androgen deprivation therapy (ADT) is highly effective in improving patient outcomes. However, around 20% of patients progress to castration-resistant disease within 12 months of treatment; these patients have shorter survival and limited treatment options. Aberrant activation of the PI3K/AKT pathway, predominately due to PTEN loss, is common in prostate cancer, especially in later-stage disease. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated such as that inhibition of one leads to upregulation of the other. Therefore, combining abiraterone therapy with AKT inhibition may be beneficial in patients with mHSPC who have PTEN deficiency. In preclinical studies, capivasertib, a selective oral pan-AKT inhibitor, inhibited proliferation of models of hormone-sensitive and castration-resistant prostate cancer with PTEN loss. The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. CAPItello-281 (NCT04493853) is a global, multicenter, phase 3 trial to evaluate capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. Methods: Eligible patients for this double-blind, randomized trial are men aged 18 years or older with confirmed newly diagnosed previously untreated metastatic hormone-sensitive prostate adenocarcinoma with immunohistochemically confirmed PTEN deficiency and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Following screening, approximately 1000 patients will be randomized 1:1 to receive either capivasertib (400 mg) or placebo (twice daily; 4 days on, 3 days off) in combination with abiraterone (1000 mg once daily) and ADT until radiographic progression or intolerable toxicity. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020. Acknowledgments: We thank Julia Grigorieva, PhD, of Oxford PharmaGenesis, Philadelphia, USA, for providing medical writing assistance. Funding: The CAPItello-281 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04493853.

Efficacy of abiraterone acetate in castration-resistant metastatic prostate cancer: A real-world data analysis.

The aim of this study was to evaluate the efficacy of abiraterone in patients with castration-resistant metastatic prostate cancer. We retrospectively analyzed 51 patients with mCRPC treated with abiraterone acetate from January 2014 to August 2018. Clinicopathological information, treatment modalities, treatment responses, and survival times were retrospectively reviewed. A total of 51 patients who received abiraterone 1000mg/day + prednisone 10mg/day between January 2014 and August 2018 were included in the study. Of these patients, 33 (64.7%) had post-chemotherapy (CT) and 18 (35.3%) had CT-naive abiraterone receipt. Median overall survival (OS) was 17.3 months (range 9.3-33.1). Median OS was found to be 12.7 months (range 9.4-18.3) and 29.4 months (range 9.3-33.0) in the CT-naive and post-CT group, respectively (P=.236). Median radiographic PFS (rPFS) was 10.1 months (range 4.5-18.4). In the CT-naive group, rPFS was 10.1 months (IQR 6.0-14.7) and in the post-CT group, it was 9.7 months (range 4.0-18.4) (P=.808). PSA progression-free survival (PSA-PFS) was 9.1 months (range 4.6-13.1). In the CT-naive group, PSA-PFS was 7.4 months (range 4.6-13.4) and in post-CT, it was 9.1 months (range 4.8-13.1) (P=.843). These results show that abiraterone acetate is an effective and reliable agent in real-life data.

610O Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations

610O Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations

Systemic treatment options for metastatic hormone-sensitive prostate cancer: making sense of the data.

Systemic treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) have recently shifted from the traditional androgen deprivation therapy (ADT) monotherapy to multidrug approaches incorporating drugs initially approved for castration-resistant state and ADT. However, clinicians have difficulties in choosing the adequate combination therapy for individualized patient care, because of the lack of consensus regarding disease risk factors, differences in study design of the major clinical trials and lack of direct comparisons between drugs. The aim of this review is to provide an update of the current treatment options for this heterogenous group of patients. Current oncological guidelines strongly recommend that patients with newly diagnosed mHSPC and high-volume disease (CHAARTED criteria) should receive docetaxel and ADT, whereas those with high-risk disease (LATITUDE criteria) abiraterone and ADT. Recently, the Food and Drug Administration approved apalutamide and enzalutamide for mHSPC. Moreover, new data support the efficacy of docetaxel and abiraterone in patients with mHSPC, regardless of metastatic burden. Today, the combination approach should be recommended for newly diagnosed mHSPC over ADT monotherapy, but treatment initiation must be personalized based on disease, drug and patient characteristics. Thanks to continuous efforts and progress in patient and disease-related outcomes, mHSPC could become a chronic disease.

Abiraterone in patients with recurrent epithelial ovarian cancer: principal results of the phase II Cancer of the Ovary Abiraterone (CORAL) trial (CRUK - A16037).

Background:Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC.Patients & Methods:CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks.Results:A total of 42 patients were recruited; median age 65 (range 34–85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays.Conclusions:CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation.Trial registration:CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050