Update on radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: clinical aspects and survival effects

2021 ◽  
pp. 030089162110377
Author(s):  
Valentina Fuoco ◽  
Giovanni Argiroffi ◽  
Stefania Mazzaglia ◽  
Alice Lorenzoni ◽  
Valentina Guadalupi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Current Data ◽  
Phase Iii ◽  
Current Evidence ◽  
Clinical Aspects ◽  
Castration Resistant Prostate Cancer ◽  
Radioligand Therapy ◽  
Treatment Protocols ◽  
Castration Resistant

Objective: To give an updated overview on clinical aspects and survival effects of lutetium-177–prostate-specific membrane antigen (PSMA) (177Lu-PSMA) radioligand therapy (RLT), a novel treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: PubMed/MEDLINE database was searched for relevant articles published up to March 2021. The search was restricted to English-language articles. Results: Current evidence from the literature consistently demonstrated the efficacy, safety, and survival benefit of 177Lu-PSMA RLT in mCRPC. However, current data rely predominantly on retrospective analyses, showing heterogeneity of patient population and treatment protocols. More recently, results from the first randomized phase II study (TheraP) demonstrated that 177Lu-PMSA therapy significantly improved prostate-specific antigen response rate (66% vs 37%) and had fewer grade 3/4 adverse events when compared to cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC. This review is intended to provide an updated overview of treatment protocols and responses, toxicity profile, and survival effects of 177Lu-PSMA RLT. Conclusions: 177Lu-PSMA RLT has emerged as a promising targeted treatment in mCRPC. It is currently applied in compassionate use programs and following exhaustion of approved therapies. Crucial for establishing this treatment in routine clinical management will be the results of the phase III VISION trial, which may confirm the encouraging patient outcomes reported to date.

scholarly journals Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel

2019 ◽  
Vol 37 (5) ◽  
pp. 403-410 ◽  
Author(s):  
Susan Halabi ◽  
Sandipan Dutta ◽  
Catherine M. Tangen ◽  
Mark Rosenthal ◽  
Daniel P. Petrylak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Black Men ◽  
Performance Status ◽  
Specific Antigen ◽  
White Men ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Black And White ◽  
Castration Resistant

Purpose Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen. Methods Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases). Results Of 8,820 men, 7,528 (85%) were white, 500 (6%) were black, 424 (5%) were Asian, and 368 (4%) were of unknown race. Black men were younger and had worse performance status, higher testosterone and prostate-specific antigen, and lower hemoglobin than white men. Despite these differences, the median OS was 21.0 months (95% CI, 19.4 to 22.5 months) versus 21.2 months (95% CI, 20.8 to 21.7 months) in black and white men, respectively. The pooled multivariable hazard ratio of 0.81 (95% CI, 0.72 to 0.91) demonstrates that overall, black men have a statistically significant decreased risk of death compared with white men ( P < .001). Conclusion When adjusted for known prognostic factors, we observed a statistically significant increased OS in black versus white men with mCRPC who were enrolled in these clinical trials. The mechanism for these differences is not known.

scholarly journals Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial

2020 ◽  
Author(s):  
Hiroji Uemura ◽  
Hisashi Matsushima ◽  
Kazuki Kobayashi ◽  
Hiroya Mizusawa ◽  
Hiroaki Nishimatsu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Sample Size ◽  
Group Analysis ◽  
Specific Antigen ◽  
Japanese Patients ◽  
Small Sample ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Abstract Background Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. Methods In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. Results In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. Conclusions Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

scholarly journals Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1

2016 ◽  
Vol 34 (25) ◽  
pp. 3005-3013 ◽  
Author(s):  
Matthew Smith ◽  
Johann De Bono ◽  
Cora Sternberg ◽  
Sylvestre Le Moulec ◽  
Stéphane Oudard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Specific Antigen ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Bone Biomarkers ◽  
End Point ◽  
Castration Resistant ◽  
Previously Treated

Purpose Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Patients and Methods Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. Results A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post–random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Conclusion Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

scholarly journals Pretreatment neutrophil-to-lymphocyte ratio and Mean Platelet Volume in castration-resistant prostate cancer patients treated with first-line docetaxel

2019 ◽  
Author(s):  
Barbaros Başeskioğlu ◽  
Berna Bozkurt Duman ◽  
Bülent Yıldız ◽  
Timuçin Çil ◽  
Murat Dinçer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mean Platelet Volume ◽  
Specific Antigen ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Platelet Volume ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Castration Resistant ◽  
Psa Response

Abstract Background:Patients who have evidence of disease progression (eg, increase in serum prostate-specific antigen [PSA], new metastases, progression of existing metastases) while being managed with androgen deprivation therapy (ADT) are considered to have castration-resistant disease. Docetaxel (75 mg/m2) given every three weeks in combination with daily prednisone (5 mg twice a day) significantly prolonged overall survival compared with mitoxantrone plus prednisone in the TAX 327 phase III trial [3]. Based upon those results, docetaxel plus prednisone has become the standard initial regimen when chemotherapy is indicated for CRPC Methods: Inflammation-based markers, such as the Neutrophile/Lymphocyte Ratio (NLR), are widely available and inexpensive measurements that are easy to integrate into pretreatment evaluation. Mean platelet volume (MPV) is a marker of activated platelets is associated some types of cancer including ovarian, gastric cancer. We retrospectively evaluated the predictive impact of neutrophil-lymphocyte ratio (NLR) and MPV as a marker for in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel.Results: A significant correlation was not observed between NLR and PSA response. A significant correlation was not also observed between MPV and PSA response.There no correlation was found between MPV and NLR with total PSA level and response (p:0.355, p:0.673 respectively)Conclusion: . In our study; We didn’t show any correlation between MWP level, NLR ratio and response to Docetaxel therapy A significant correlation was not also observed between NLR , MPV and PSA response.

Apalutamide, darolutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer: a meta-analysis

2021 ◽  
Author(s):  
Mathieu Roumiguié ◽  
Xavier Paoletti ◽  
Yann Neuzillet ◽  
Romain Mathieu ◽  
Sebastien Vincendeau ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Meta Analysis ◽  
Specific Antigen ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Phase Iii Clinical Trials ◽  
Castration Resistant ◽  
Related Quality ◽  
Health Related

Aim: Comparison of the efficacy/safety/health-related quality of life of apalutamide, enzalutamide and darolutamide in Phase III clinical trials involving patients with nonmetastatic castration-resistant prostate cancer was performed. Materials & methods: Relevant studies were identified by searching PubMed as well as conference abstracts reporting updated overall survival. Three pivotal trials were identified, SPARTAN (apalutamide), PROSPER (enzalutamide) and ARAMIS (darolutamide), and form the basis of this analysis. Results: All three drugs significantly prolonged metastasis-free survival, prostate-specific antigen response and overall survival versus placebo, and were generally well tolerated. Conclusion: Drug selection will likely be influenced by tolerability/safety and other factors, such as the propensity for drug–drug interactions and the presence of comorbidities, that affect the risk–benefit balance in individual patients.

Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial

2016 ◽  
Vol 34 (18) ◽  
pp. 2098-2106 ◽  
Author(s):  
David F. Penson ◽  
Andrew J. Armstrong ◽  
Raoul Concepcion ◽  
Neeraj Agarwal ◽  
Carl Olsson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Cancer Progression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Beneficial Effects ◽  
Castration Resistant

Purpose Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC. Patients and Methods A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS). Results Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio [HR], 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials. Conclusion Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.

scholarly journals NEW TREATMENT STANDARD FOR PATIENTS WITH NON-METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

2018 ◽  
Vol 14 (3) ◽  
pp. 68-77
Author(s):  
B. Ya. Alekseev
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Group Versus ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Castration Resistant ◽  
Treatment Standard ◽  
New Treatment

Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen level are at high risk for metastasis. Until recently there was no standard of treatment for this category of patients. A total of 1401 patients with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less underwent randomization to double-blind, phase III PROSPER trial. Patients were continuing androgen-deprivation therapy in combination with enzalutamide (at a dose of 160 mg) or placebo once daily. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group. Enzalutamide treatment resulted in a 71 % lower risk of radiographic progression or death than did placebo (hazard ratio 0.29; 95 % confidence interval 0.24 to 0.35; p <0.001). Adverse events were consistent with the established safety profile of enzalutamide.

Previous enzalutamide therapy and response to subsequent taxane therapy in metastatic castration-resistant prostate cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 227-227 ◽  
Author(s):  
Marco Gizzi ◽  
Giulia Baciarello ◽  
Aude Flechon ◽  
Philippe Beuzeboc ◽  
Antoine Angelergues ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase Iii ◽  
Cross Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Response ◽  
Pretreated Patients ◽  
The Impact

227 Background: Cross-resistance between taxanes and androgen receptor axis targeted agents is a matter of debate in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data about response to taxanes after prior enzalutamide suggest some level of cross-resistance (van Soest et al, Eur J Cancer 2013) though this was not confirmed in other models (Al Nakouzi N, Eur Urol 2014). The first objective of this study was to assess the impact of previous enzalutamide therapy on the efficacy of subsequent taxane-based chemotherapy. The second objective was to investigate the prognosis of patients when chemotherapy was initiated in enzalutamide-pretreated patients. Methods: Data from 96 enzalutamide- and placebo-treated patients enrolled in the Prevail phase III trial were retrospectively collected from 14 centers in France. Changes in prostate specific antigen (PSA) levels, progression free survival (PFS) and RECIST criteria v 1.1 were used to determine the activity of docetaxel (n=89) or cabazitaxel (n=7) treatment. The Halabi model was used to predict survival probabilities for the enzalutamide- or placebo-pretreated patients when chemotherapy was initiated (Halabi et al, J Clin Oncol 2014). Results: Overall, 96 patients were included in this analysis (58 in the placebo arm vs. 38 in enzalutamide arm). PSA response to taxanes (defined as a decline of ≥50% from baseline) was marginally lower in enzalutamide-vs. placebo-pretreated patients (34% vs. 53%, p=0.10). PSA response in enzalutamide-pretreated patients was not different from that observed with docetaxel given every 3 weeks in TAX 327 trial (Tannock et al, NEJM 2004) (45%, p=0.20, binomial test). Median PFS and objective response rates were similar between the two groups (4.8m vs 6.7 m;p=0.14 and 45% vs 43%;p=0.83 respectively). Halabi score was well-balanced between the two groups (p=0.30). Conclusions: Taxanes retain efficacy in enzalutamide-pretreated mCRPC. At the time of first-line taxane-based chemotherapy initiation, the prognosis of enzalutamide-treated patients according to the Halabi score was not different from that of enzalutamide-naïve patients.

DAROL: DARolutamide ObservationaL study patients in nonmetastatic castration-resistant prostate cancer (nmCRPC) patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5593-TPS5593
Author(s):  
Evan Y. Yu ◽  
Christopher Michael Pieczonka ◽  
Alberto Briganti ◽  
Declan G. Murphy ◽  
Thierry Lebret ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Real World ◽  
Specific Antigen ◽  
Clinical Effectiveness ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Event Time ◽  
Castration Resistant ◽  
The Us

TPS5593 Background: Patients (pts) with prostate cancer treated with prolonged androgen deprivation therapy (ADT) will eventually develop castration-resistant disease. Treatment of pts with nmCRPC with darolutamide (DARO) delays the development of metastases, which are associated with cancer-related morbidity. DARO is a structurally unique oral androgen receptor inhibitor approved by the FDA for the treatment of nmCRPC, based on prolonged metastasis-free survival (MFS) compared with placebo (median 40.4 months vs.18.4 months, respectively) in the ARAMIS phase III clinical trial. DARO showed a similar incidence of adverse events (AEs) compared to ADT alone and has a low potential for drug-drug interactions. However, phase III clinical trials cannot fully reflect all the facets of real-world pts. Therefore, non-interventional studies in the real-world setting, such as DAROL, are able to provide additional insight into the patterns of use and real-world safety profile of recently approved drugs. Methods: (NCT04122976) will enrol participants in the US, Brazil, Japan, and the EU. Eligible pts include men with histologically confirmed nmCRPC aged ≥18 yrs, life expectancy ≥3 months, and initiated on DARO treatment as per investigators’ decision within 3 days prior to enrollment. DAROL opened for enrollment in December 2019 in the US with a projected enrollment of 1000 pts. The primary endpoint of DAROL is safety. Treatment-emergent AEs will be collected during the study. Secondary endpoints to measure clinical effectiveness are MFS, time to symptomatic skeletal event, time to prostate-specific antigen progression, survival rate, and duration of DARO therapy. Other endpoints include pt demographics and characteristics, and prior and subsequent therapy. The estimated primary completion date is December 30, 2024. Clinical trial information: NCT04122976 .

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