Docetaxel and imatinib every 21 days for castration resistant prostate cancer: A phase II trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16086-e16086
Author(s):  
T. L. Gillison ◽  
L. J. Appleman ◽  
D. M. Friedland ◽  
T. L. Evans ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Castration Resistant Prostate Cancer ◽  
Meaningful Improvement ◽  
Neutropenic Sepsis ◽  
Significant Toxicity ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

e16086 Background: Docetaxel (D) IV every 21 days, is the only cytotoxic agent that prolongs survival in men with castrate resistant prostate cancer (CRPC). Imatinib (I), a tyrosine kinase inhibitor, modulates PDGFR-ß in tumor vasculature. Based on phase I data from our institution, we hypothesized that D plus I would prolong time to progression (TTP) in patients (pts) with CRPC. Methods: Subjects with CRPC received D 60 mg/m2 IV every 21 days plus I 400 mg PO daily. After 10 pts, the study treatment was modified due to toxicity so that pts received I 400 mg on 10 of 21 days/cycle. The primary endpoint was TTP. Secondary endpoints were rate of PSA response and overall survival (OS). The sample size of 43 pts was designed to provide 90% power to detect an increase in TTP from 5 to 8 months. Results: 43 pts enrolled from 8/05 to 9/08. Age at enrollment ranged from 54–86 years (median 69 years). 14 pts received <1 cycle of D plus I and were unevaluable: 10 had significant toxicity, 4 due to non-treatment related reasons. Primary toxicities were hematologic: 21% G4 neutropenia, 5% G4 anemia, and no G4 thrombocytopenia. Fatigue, nausea, diarrhea, and electrolyte abnormalities were common, but <2 cases each of G3-G4 toxicity occurred. 1 case of G5 non-neutropenic sepsis occurred. 29 pts received >2 cycles of chemotherapy (mean 4.6). 12 pts had PR (41.4%), 9 had SD (31.0%), and 8 had no response (27.6%) by PSA. No objective responses were seen by CT imaging among 10 pts with measurable disease. 3 pts remain on trial. For evaluable pts, overall median TTP was 6.4 months (95% CL: 4.8, 8.4 months) compared with TTP of 5 months seen in previous trials. 23 (79%) pts had PSA progression, 3 pts died before progression, and 3 pts remain on trial. For all evaluable pts who had PR or SD by PSA (N = 21), median TTP was 7.1 months (95% CL: 5.5, 9.1 months). Median OS was 23.1 months (95% CL: 11.61 months, NR), compared with 18.9 months for GC Conclusions: Docetaxel on day 1 plus imatinib 10 days of each 21-day cycle resulted in meaningful improvement in TTP in the subset of pts who showed a response. Toxicity precludes its use in the general population, although its role in select pts with good performance status needs to be explored. [Table: see text]

βIII-tubulin expression as a predictor of docetaxel resistance in metastatic castrate-resistant prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15174-e15174
Author(s):  
Bertha E. Sanchez ◽  
Nilesh Gupta ◽  
Meredith Mahan ◽  
Evelyn R Barrack ◽  
Prem-veer Reddy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Clinical Decision Making ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Docetaxel Resistance ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
The Mean ◽  
Castrate Resistant

e15174 Background: Docetaxel is a tubulin-targeting cytotoxic that remains first-line therapy in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) even though half of pts are reported to be non-responders. A predictive marker to identify those who will benefit from docetaxel-therapy will assist clinical decision making. High βIII-tubulin (TUBB3) expression has previously been reported to correlate with lack of response to taxanes in other cancers. We evaluated TUBB3 expression as a predictor of docetaxel-resistance in mCRPC. Methods: mCRPC pts treated with at least 3 cycles of docetaxel between 1990 and 2011 were identified retrospectively. TUBB3 immunostaining was performed on archival formalin-fixed, paraffin-embedded tissue. Stain intensity was scored from 0 to 3; 2 and 3 were interpreted as positive. Rates of PSA response were compared between pts with positive (+) and negative (-) TUBB3 expression. Two definitions of PSA response were evaluated (any PSA decline and at least 50% decline). Overall survival (OS) distribution between TUBB3+ and TUBB3- pts was estimated by the Kaplan-Meier method. Results: Of 73 pts, 26 (35%) expressed TUBB3. At diagnosis, the mean age was 65.7 years and the median Gleason score was 8. At the time of docetaxel therapy, the mean age was 71.2 years, the median PSA level was 70.9 (range, 0.2-5253) and 76% had ECOG performance status ≤1. The median number of docetaxel cycles was 7 (range, 3-18). The total dose of docetaxel was not different between groups (p=0.705). The median OS was 19.2 mo. TUBB3 expression was not correlated with any clinical or pathological characteristic (age, Gleason score, stage, ECOG, PSA, LDH, alkaline phosphatase, hemoglobin, visceral disease or chemotherapy before docetaxel). 65% of TUBB3+ pts had any PSA decline compared to 89% of pts with TUBB3- (p=0.0267). 52% of TUBB3+ pts had a PSA decline of ≥ 50% compared to 70% of TUBB3- pts (p=0.0144). Median OS for TUBB3+ pts was 16.8 mo compared to 20.4 mo in TUBB3- pts (p=0.039). Conclusions: High TUBB3 expression was associated with shorter OS and lower PSA response rates in mCRPC pts treated with docetaxel. These findings need to be validated prospectively.

Development of a predictive model of PSA response to a switch from prednisone to dexamethasone in metastatic castrate-resistant prostate cancer patients biochemically progressing on abiraterone.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 88-88
Author(s):  
Reeta Barua ◽  
Cameron Phillips ◽  
Vanessa Sarah Arciero ◽  
Liying Zhang ◽  
Amanda Rahmadian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Logistic Regression ◽  
Regression Analysis ◽  
Performance Status ◽  
Multivariable Logistic Regression Analysis ◽  
Ecog Performance Status ◽  
Disease Characteristics ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

88 Background: Abiraterone acetate (AA) is typically administered with prednisone (P) to prevent symptoms of mineralocorticoid excess in patients with metastatic castrate resistant prostate cancer (mCRPC). After biochemical progression on AA + P, there is a sizeable subset of patients who have a renewed PSA response when switched from P to dexamethasone (D). The purpose of this study was to delineate clinical and pathologic factors that are predictive of a PSA response to such a steroid switch. Methods: We performed a retrospective analysis of 87 patients switched from AA+P to AA+D at Sunnybrook Odette Cancer Centre (Toronto, ON, Canada) between December 2012 and September 2018. Information on demographics, disease characteristics, previous treatments and performance status was collected. Response to the P to D switch maneuver was defined as a decrease in PSA by ≥30% within 12 weeks of the intervention (PSA30). Univariate logistic regression analyses were used to create a prediction model for each covariate tested, and R2 was applied for the measure of fit.Using multivariable logistic regression analysis and a backward stepwise selection procedure, we sought to identify patient and/or disease characteristics associated with a PSA30. Results: 38/87 patients (44%) experienced a PSA30. Univariate analysis showed that a favourable ECOG performance status, no prior docetaxel and no prior enzalutamide use were associated with a PSA30. On multivariable logistic regression analysis both favourable ECOG performance status and no prior enzalutamide use remained associated with a PSA30 (Table). Conclusions: A considerable proportionof patients with mCRPC who biochemically progress on AA+P have a renewed PSA response when changed to AA+D.Patients with a favourable ECOG performance status and no prior enzalutamide use are more likely to respond to such a steroid switch. Further prospective studies are needed to validate our findings.[Table: see text]

Enzalutamide after failure of docetaxel and abiraterone in metastatic castrate resistant prostate cancer (mCRPC): Results from an expanded access program.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 188-188 ◽  
Author(s):  
David Thomson ◽  
Natalie Charnley ◽  
Omi Parikh
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Progression Free Survival ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Biochemical Progression ◽  
Castrate Resistant ◽  
Access Program

188 Background: Abiraterone or enzalutamide are licensed for use post-docetaxel in metastatic castrate resistant prostate cancer (mCRPC). Both target the androgen receptor signalling pathway. There is little information describing their sequential use. Methods: Patients with mCRPC who had failed treatment with docetaxel and abiraterone received enzalutamide as part of an expanded access program. Patients were reviewed four weekly and post-treatment PSA used to determine efficacy. Results: Twenty three patients, median age 76 (range, 65 to 82), performance status of 1 (15/23) or 2 (8/23) with mCRPC (22/23 bone and 4/23 visceral disease) were enrolled. All had received prior docetaxel and abiraterone as well as cabazitaxel (35%), dexamethasone (30%), and stillboestrol (52%). Median biochemical progression free survival (bPFS) was 11.9 weeks. Nine (39%) patients showed sensitivity to enzalutamide, defined as a greater than 50% reduction in PSA. There was a correlation between PSA response to abiraterone and enzalutamide (R=0.45, p=0.03). In 10 out of 23 and 13 out of 23 patients who were sensitive and insensitive to abiraterone, 60% and 23% had a great than 50% reduction in PSA, respectively. There was a trend to improved bPFS in those sensitive to abiraterone (15.7 vs. 11.4 weeks, p=0.40) and in those who showed any PSA response to abiraterone (15.9 vs. 5.3 weeks, p=0.06). Conclusions: Enzalutamide has activity following failure of docetaxel and abiraterone in mCRPC. The effectiveness is more pronounced in those who have responded to abiraterone.

Evaluating the impact of bone-targeted agents in the era of novel androgen targeted therapy for metastatic castration-resistant prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16500-e16500
Author(s):  
Haoran Li ◽  
Dalia Kamel ◽  
Ricardo Fernandes ◽  
Dominick Bosse ◽  
Dong Vo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Bone Metastases ◽  
Real World ◽  
Smoking History ◽  
Castration Resistant Prostate Cancer ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Impact

e16500 Background: Patients with metastatic castrate resistant prostate cancer (mCRPC) often develop bone metastases, resulting in a risk of symptomatic skeletal events (SSE). Bone-targeted agent (BTA) has been integrated into the overall treatment strategy, but its role in the era of novel androgen-targeted therapy (ATT) is still unclear. Methods: A retrospective analysis of real-world practice from 2010 to 2015 was conducted. Patients diagnosed with mCRPC and bone metastases who received systemic therapy (docetaxel/abiraterone/enzalutamide) with or without BTA (zoledronic acid/denosumab/alendronate) were included. Results: We obtained data from 299 patients with a median follow-up of 75.5 months. Compared with no BTA, concomitant BTA was associated with decreased incident of SSE (3.8% vs. 19.2%, p< 0.001), especially in the need for bone radiation (1.9% vs. 15.8%, p< 0.001). Compared to patients without SSE, patients with SSE were more likely to have previous fracture history (10.8% vs. 9.7%, p= 0.047), steroid use history (2.4% vs. 1.4%, p= 0.019), smoking history (53.0% vs. 38.9%, p= 0.009), diabetes (19.3% vs. 8.8%, p= 0.012) and reduced baseline mobility (9.6% vs. 4.2%, p= 0.002). Among those who received first-line novel ATT (n = 152), concurrent ATT+BTA significantly decreased the incident of SSE (2.8% vs. 27.3%, p= 0.004) and prolonged the time to SSE (24.3 vs. 3.2 mo, p< 0.001), when compared to ATT alone. But there was no difference in overall survival between two groups (134.2 vs. 138.9 mo, p= 0.99). In patients who responded to systemic treatment with PSA declining, the SSE rate (2.4% vs. 14.3%, p= 0.037) was lower and the time to SSE was longer (49.6 vs. 32.3 mo, p= 0.026) than those who did not respond. Smoking history (adjusted HR = 1.46, p= 0.013) and PSA response (adjusted HR = 0.19, p< 0.001) are independent risk factors for SSE. Conclusions: This real-world database suggests that concomitant BTA with novel ATT was associated with reducing SSEs. PSA decrease might be used as a predictive factor for those under BTA treatment. Further studies are warranted to validate the role of PSA response.

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.

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.

scholarly journals Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 884
Author(s):  
Steven K. Nordeen ◽  
Lih-Jen Su ◽  
Gregory A. Osborne ◽  
Perry M. Hayman ◽  
David J. Orlicky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Dose ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Ablation ◽  
Clinical Observations ◽  
Clinical Benefits ◽  
Castrate Resistant Prostate Cancer ◽  
Prostate Cancers ◽  
Castrate Resistant ◽  
Basic Studies

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits.

Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 205-205
Author(s):  
Joseph R. Bertino ◽  
Zoltan Szekely ◽  
Kathleen W Scotto
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Replication Proteins ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Stability

205 Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.

A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS394-TPS394 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Ralph de Vere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Androgen Synthesis ◽  
Psa Response

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.

The use of intermittent enzalutamide dosing in the treatment of metastatic castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 81-81
Author(s):  
Michael Rowe ◽  
Ayesha Hidayat ◽  
Stuart Walter ◽  
Adam Pollard ◽  
Timothy Norris ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Time ◽  
Median Number ◽  
Significance Level ◽  
Kaplan Meier ◽  
Single Centre Study ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Continuous Scheduling

81 Background: Intermittent hormone manipulation in castrate-sensitive prostate cancer can improve quality of life whilst maintaining comparable disease outcomes with continuous scheduling. Enzalutamide is effective in metastatic castrate-resistant prostate cancer (mCRPC) treatment but can have significant side-effects. We conducted a retrospective analysis of patients treated with intermittent enzalutamide compared with continuous dosing. Methods: Patients prescribed enzalutamide for mCRPC at Royal Cornwall Hospital from September 2011 to February 2018 were included. Data was collected from electronic medical records, selecting patients with at least a 1 month treatment break. Kaplan-Meier analysis of overall survival from enzalutamide start (OS), time to PSA failure (TTF) and total enzalutamide treatment time (TTT) was calculated for intermittent and continuous responders (>50% PSA drop), assigned significance level of 0.05. Results: 243 patients received enzalutamide, 110 (45%) were continuous responders and 29 (12%) had intermittent dosing. All patients treated intermittently had a PSA response prior to first treatment break, which was most commonly for fatigue (60%). 25% were still receiving enzalutamide. Median number of breaks was 1 (range 1-7), time on treatment was 70% and time to first break was 5 months. The intermittent group had significantly improved OS with median not reached, median OS for continuous responders was 19 months (HR 2.39, 95% CI 1.53-3.76, p=0.002). The intermittent group had prolonged TTF (median 13 vs 6 months, p=0.001) and TTT (median 30 vs 10 months, p=0.0003). Conclusions: Intermittent dosing of enzalutamide in these mCRPC patients does not adversely impact OS, increasing time patients remain on treatment. However, this was a small, retrospective, single-centre study; prospective trials are necessary to clarify the role of intermittent enzalutamide.[Table: see text]

scholarly journals Bone-Targeted Therapies in Metastatic Castration-Resistant Prostate Cancer: Evolving Paradigms

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Joelle El-Amm ◽  
Ashley Freeman ◽  
Nihar Patel ◽  
Jeanny B. Aragon-Ching
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Kinase Inhibitors ◽  
Targeted Agents ◽  
Pain Palliation ◽  
Castration Resistant Prostate Cancer ◽  
Humanized Monoclonal Antibody ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Overall Survival Benefit

Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases.

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