The sequential use of abiraterone and enzalutamide (MDV3100) in castrate resistant prostate cancer patients: Experience from Birmingham, United Kingdom.

e16048 Background: Phase III studies have demonstrated survival benefits from abiraterone1 (Abi), and Enzalutamide2 (MDV3100; Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enzalutamide (Enz) is available, via early access scheme, for progressive disease post docetaxel, regardless of prior Abi exposure. There has been no randomised trial on sequential usage of Enz post Abi. We therefore report our experience. Methods: We searched our pharmacy database for patients who have received Enz and identified 51 patients who started treatment between the 2nd August 2012 and 10thJanuary 2013. A detailed notes review was carried out of these patients. Results: Median age was 76 (range 55-87) years. All patients had received androgen deprivation therapy and Docetaxel. 46 patients had received previous Abi, 38 of patients’ receiving Abi as the last treatment prior to Enz. At the time of submission 10 patients had stopped Enz due to PSA progression with a mean TTP of 15 weeks (range 7-22) and 6 patients had died; 2 from disease progression (mean TTP 3.5 weeks). For the 30 patients still on Enz, the mean duration of treatment was 16.47 weeks (range 4-27). 33 patients didn't report any significant side effects associated with Enz treatment. The most common side effect was fatigue (23.6%); 3 patients (6%) experiencing G3 fatigue. Other reported side effects included diarrhoea (4%), nausea (6%), confusion (6%), anxiety (6%), depression (6%), hallucinations (2%) and insomnia (2%). 3 patients (6%) had Enz stopped due to G3 fatigue. Conclusions: The AFFIRM study demonstrated TTP of 8.3 months (36 weeks) in patients post-docetaxel2. In this audit the TTP of patients receiving Enz post-Abi was 15 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. However, longer follow-up of the 30 patients currently taking Enz is required. The number of patients experiencing G3 fatigue was the same as reported in AFFIRM, but there were a surprising number of patients experiencing psychiatric side-effects.

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The sequential use of abiraterone and enzalutamide in metastatic castrate resistant prostate cancer patients: Experience from seven U.K. centers.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.125 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 125-125 ◽

Cited By ~ 6

Author(s):

Robert Stevenson ◽

David Gareth Fackrell ◽

Daniel Ford ◽

John Glaholm ◽

Ahmed El-Modir ◽

...

Keyword(s):

Prostate Cancer ◽

Randomised Trial ◽

Specific Antigen ◽

Phase Iii ◽

Early Access ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

The Uk ◽

Taxane Chemotherapy ◽

Patients Experience

125 Background: Phase III studies have demonstrated survival benefits from abiraterone (Abi), and enzalutamide (Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is now available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enz has recently become available, via the UK cancer drugs fund (CDF), for progressive disease post docetaxel, prior to exposure to Abi. There has been no randomised trial on sequential usage of Enz post-Abi. We therefore, report the experience of hospitals in Coventry, Cardiff, and five centers in Birmingham. Methods: We searched the pharmacy database for patients who have received Enz as part of an early access scheme, and identified 79 patients who started treatment between the August 2012 and April 2013. A detailed notes review was carried out of these patients. Results: Median age was 74 (range of 55 to 87). All patients had received hormone androgen deprivation therapy and taxane chemotherapy (docetaxel and/or cabazitaxel) 75 patients had received previous Abi, 62 of these patients receiving Abi as the last treatment prior to Enz. The mean time to progression (TTP) for Abi in these 62 patients was 37.44 weeks (range 4 to 104). At the time of submission 55 patients had stopped Enz due to prostate-specific antigen progression with a mean TTP of 15.87 weeks and 28 patients had died. Conclusions: The AFFIRM study demonstrated TTP of 36 weeks in patients post-docetaxel. In this audit of patients receiving Enz post-Abi the TTP was only 15.87 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. Trials are underway comparing Abi alone or in combination with Enz which may improve efficacy.

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Association of health-related quality of life (HRQOL) variations with biological biomarkers for patients with metastatic castrate-resistant prostate cancer (MCRPC) treated by abiraterone/prednisone combination or prednisone.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.54 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 54-54

Author(s):

Morgan Goujon ◽

Amelie Anota ◽

Alexandre Frontczak ◽

Emilie Charton ◽

Tristan Maurina ◽

...

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Phase Iii ◽

Health Related Quality ◽

Meaningful Improvement ◽

Related Quality ◽

Health Related ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

54 Background: A potential link between Health-Related Quality of life (HRQoL) and oncologic outcomes such as overall survival or progression-free survival has been underlined for endocrine therapies in patients with metastatic castrate resistant prostate cancer (mCRPC). Other surrogates such as circulating tumor cells (CTCs) or PSA can be used to evaluate disease control. This study explored the associations between HRQoL and biological biomarkers for patients with mCRPC treated by abiraterone / prednisone or prednisone within registration phase III trial COU-AA-301. Methods: Baseline differences of HRQoL evaluated with FACT-P total score (FACT-P TS) according to biological parameters (including CTCs and PSA) and links between HRQoL's change and variations of these parameters were assessed. The primary objective was to estimate the association between improvement or deterioration in FACT-P TS and the variations of CTCs and PSA. All analyses were conducted using clinically meaningful improvement and deterioration in FACT-P TS and subscales. Results: Among 1130 patients enrolled, 1111 (98.3%) had a baseline FACT-P TS available. At baseline, a favorable CTCs count was associated with higher FACT-P TS compared to unfavorable CTCs (difference in means 8 points, [95% CI, 4 to 12] p < 0.001). At 3 months, there were differences in mean change from baseline FACT-P TS favoring patients with biomarkers response, with clinically meaningful difference for CTCs (12.7 points, [95% CI, 6 to 19.5%] p < 0.001) and PSA (11.64 points, [95% CI, 9.3 to 14] p < 0.0001). Biological progression was associated with higher risk of FACT-P TS worsening for PSA (Odds Ratio (OR) 2.8 [95% CI, 1.9 to 4.2]) with more frequent FACT-P TS improvement in case of response for CTCs (OR 3.14 [95% CI, 1.3 to 7.7]) and PSA (OR 2.9 [95% CI 2.1 to 4]). Significantly longer time until definitive deterioration was observed for patients with CTCs or PSA response (p < 0.001) and shorter time in case of progression (p < 0.001). Conclusions: QUA-lify is the first study to show an association between HRQoL and biomarkers outcomes in patients with mCRPC treated with endocrine therapy in a post-taxane setting. This concept is reinforced by the consistency of the association for all analyses carried out.

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Heterogeneous ensembles for predicting survival of metastatic, castrate-resistant prostate cancer patients

F1000Research ◽

10.12688/f1000research.8231.2 ◽

2017 ◽

Vol 5 ◽

pp. 2676 ◽

Cited By ~ 3

Author(s):

Sebastian Pölsterl ◽

Pankaj Gupta ◽

Lichao Wang ◽

Sailesh Conjeti ◽

Amin Katouzian ◽

...

Keyword(s):

Prostate Cancer ◽

Survival Analysis ◽

Ensemble Methods ◽

Phase Iii ◽

Survival Models ◽

Phase Iii Clinical Trials ◽

Wide Range ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Heterogeneous Ensemble

Ensemble methods have been successfully applied in a wide range of scenarios, including survival analysis. However, most ensemble models for survival analysis consist of models that all optimize the same loss function and do not fully utilize the diversity in available models. We propose heterogeneous survival ensembles that combine several survival models, each optimizing a different loss during training. We evaluated our proposed technique in the context of the Prostate Cancer DREAM Challenge, where the objective was to predict survival of patients with metastatic, castrate-resistant prostate cancer from patient records of four phase III clinical trials. Results demonstrate that a diverse set of survival models were preferred over a single model and that our heterogeneous ensemble of survival models outperformed all competing methods with respect to predicting the exact time of death in the Prostate Cancer DREAM Challenge.

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Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5057 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5057-5057

Author(s):

Susan Halabi ◽

Akash Roy ◽

Qian Yang ◽

Wanling Xie ◽

William Kevin Kelly ◽

...

Keyword(s):

Prostate Cancer ◽

Radiographic Progression ◽

Progression Free Survival ◽

Surrogate Endpoint ◽

Phase Iii ◽

Random Assignment ◽

Moderate Correlation ◽

Free Survival ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

5057 Background: Radiographic progression-free survival (rPFS) is commonly used as a co-primary endpoint in randomized clinical trials in men with metastatic castrate-resistant prostate cancer (mCRPC). However, rPFS has not been established as a valid surrogate endpoint of overall survival (OS) in men with mCRPC. Here, we hypothesized that rPFS is a reliable surrogate for OS in mCRPC. We also explored whether PFS is a valid surrogate endpoint of OS at the aggregate trial level. Methods: We performed a systematic search of the literature encompassing the period January 2004-December 2020 using PubMed and clinical trials.gov to identify completed phase III trials in mCRPC post-docetaxel. Eligible trials had to be randomized phase III therapeutic trials that reported OS, PFS or rPFS. OS was measured from the date of random assignment to date of death from any cause or date of last follow-up. rPFS was defined as the time from random assignment to date of disease progression on CT and/or Tc bone scan per trial definition or death from any cause, whichever occurred first. PFS included PSA progression as a component of the composite endpoint. Trial level surrogacy was evaluated by fitting linear regression on the treatment effect of rPFS (or PFS) and OS (in other words, the weighted linear regression of the log(hazard ratio) of OS on the log(hazard ratio) of rPFS). It was pre-specified that rPFS would be considered a valid surrogate for OS if R² was 0·7 or higher. Results: We identified 33 in men with mCRPC post docetaxel approval. We assessed the association between PFS and OS in 29,456 patients from 30 trials. Overall, a moderate correlation was observed at the trial level between OS and PFS ( R2 = 0.46, 95 %CI = 0.20-0.68) in these trials. In 18 trials with 16,818 mCRPC patients where rPFS was considered as a key endpoint, a moderate correlation between the treatment effects on rPFS and OS was observed at the trial level ( R2= 0.65, 95% CI = 0.23-0.87). Conclusions: This meta-analysis demonstrates moderate correlation between treatment effects of rPFS and OS in patients with mCRPC. However, rPFS did not meet the pre-specified surrogacy threshold of 0.7. Clinical trial information: several.

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7002 ORAL Time to Disease-related Pain After Sipuleucel-T in Asymptomatic Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC): Results From 3 Randomized Phase III Trials

European Journal of Cancer ◽

10.1016/s0959-8049(11)71953-0 ◽

2011 ◽

Vol 47 ◽

pp. S484 ◽

Cited By ~ 3

Author(s):

E.J. Small ◽

C.S. Higano ◽

P.W. Kantoff ◽

J.B. Whitmore ◽

M.W. Frohlich ◽

...

Keyword(s):

Prostate Cancer ◽

Phase Iii ◽

Asymptomatic Patients ◽

Phase Iii Trials ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

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Patient-reported outcomes with metastatic castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.34_suppl.207 ◽

2018 ◽

Vol 36 (34_suppl) ◽

pp. 207-207

Author(s):

Jimmy Mullally ◽

Christopher Davella ◽

Rahul Atul Parikh ◽

G J. Van Londen ◽

Leonard Joseph Appleman

Keyword(s):

Prostate Cancer ◽

Cognitive Impairment ◽

Disease Progression ◽

Well Being ◽

Open Label ◽

Hormonal Function ◽

Patient Reported ◽

Data Points ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

207 Background: Prostate cancer accounts for approximately 10% of cancer deaths in men worldwide. Clinical trials for metastatic castrate resistant prostate cancer (mCRPC) have established survival benefit with use of abiraterone (ABI) with prednisone or enzalutamide (ENZ). Despite their wide utilization, little is known about patient quality-of-life (QOL) outcomes for these agents. Our study evaluates patient reported QOL while taking ENZ or ABI/prednisone. Methods: 22 mCRPC patients were enrolled in an open label, nonrandomized manner to receive oral ENZ (n=12) or ABI/prednisone (n=6) per oncologist’s discretion. Patients completed multiple QOL validated questionnaires, including EPIC-26, FACT-P, and FACT-COG at baseline, 1,2,3,6,9 and 12 months or until progression/change of therapy. Surveys were scored by treatment group using mean, median, range, and standard deviations. QOL parameters were compared between the two groups with two-sided, two-sample T test and linear mixed models. Results: Surveys discontinued prior to 1 year secondary to disease progression/change of therapy were 58% and 33% for ENZ and ABI, respectively. By month 3, 50% of surveys were returned for ENZ and 33% for ABI. Month-to-month comparisons of QOL parameters including urinary irritation, incontinence, bowel, sexual, hormonal function, and overall well-being showed no significant differences between treatment groups or different rates of change. Perceived Cognitive Impairment was significantly lower for patients on ABI in month 3, yet Perceived Cognitive Ability favored ENZ in months 2 and 3. All other data points for cognition showed no significant differences. Conclusions: Data from FACT-COG shows discordance in perceived Cognitive Impairment and Abilities between ENZ and ABI in months 2-3. Other QOL domains indicated no difference between the two groups. The study was limited by a significant portion of patients with disease progression/change of therapy. For those on therapy, survey compliance remained high. Thus, the use of questionnaires is a feasible means of assessing patient outcomes and can be adapted to larger studies.

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Addition of carboplatin to chemotherapy regimens for metastatic castrate-resistant prostate cancer in post-second generation hormone therapy setting: Does it improve treatment response and survival outcomes?

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17540 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17540-e17540

Author(s):

Jamal Alamiri ◽

Mohamed E. Ahmed ◽

Jack R. Andrews ◽

Manaf Alom ◽

Giovanni Motterle ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Hormone Therapy ◽

Disease Progression ◽

P Value ◽

Versus Group ◽

Group A ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Group B

e17540 Background: The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after treatment with 2nd generation hormone therapy (2nd-HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing 2nd-HT. We sought to evaluate three common chemotherapy regimens in this setting. Methods: We retrospectively identified 150 patients with mCRPC with disease progression on enzalutamide or abiraterone. 92 patients were chemo-naïve, while 58 patients had previously received docetaxel chemotherapy prior to 2nd-HT. After failing 2nd-HT, 90 patients received docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). Favorable response was defined by ≥50% reduction in PSA level from baseline after a complete course of chemotherapy. Survival outcome was assessed for 30-month overall survival. Results: Mean (SD) age was 71.2 (8.28), 69.5(8.38) and 67.2 (8.36) for group (A), (B) and (C), respectively. Mean (SD) pre-chemotherapy PSA was 63.8 (138.18), 58.5 (118.15) and 53.7 (88.15) for group (A), (B) and (C), respectively. Mean (SD) Gleason score was 7.9 (1.1), 8.4 (0.88) and 8.1 (1.06) for group (A), (B) and (C), respectively. Patients in group (B) were 2.6 times more likely to have a favorable response compared to group (A) (OR = 2.625, 95%CI: 1.15 - 5.99) and almost 3 times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04 – 8.54) (p-value = 0.0442). We report a Hazard Ratio (HR) of 3.1 (95% CI 1.31-7.35; p = 0.0037) between patients in group (A) versus group (B), and a HR of 4.18 (95% CI 1.58-11.06; p = 0.0037) between patients in group (C) versus group (B). Thirty-month overall survival was 70.7%, 38.9%, and 30.3% for group (B), (A), and (C) respectively (p-value = 0.008). Conclusions: Our data demonstrate improved response and cancer-specific survival in patients with treatment-refractory mCRPC on docetaxel plus carboplatin compared to docetaxel or cabazitaxel alone. Selection bias is inherent in any retrospective study; however, our finding suggests that clinicians may consider docetaxel plus carboplatin in mCRPC patients who fail 2nd-HT. Further prospective studies are warranted.

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New Therapeutics to Treat Castrate-Resistant Prostate Cancer

The Scientific World JOURNAL ◽

10.1155/2013/379641 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Ömer Acar ◽

Tarık Esen ◽

Nathan A. Lack

Keyword(s):

Prostate Cancer ◽

Late Stage ◽

Endocrine Disruptor ◽

Patient Survival ◽

Abiraterone Acetate ◽

Phase Iii ◽

Bone Targeting ◽

Phase Iii Trials ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

The effective treatment of castrate-resistant prostate cancer (CRPC) has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.

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