Phase III study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone acetate (abi)–pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-921.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS262-TPS262 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Neal D. Shore ◽  
Mostefa Bennamoun ◽  
Raffaele Ratta ◽  
Josep M. Piulats ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Agent ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
End Points ◽  
Biomarker Analysis ◽  
Psa Response ◽  
Modified Recist ◽  
Ecog Ps

TPS262 Background: Docetaxel is an established treatment for pts with mCRPC. Pembro, a PD-1 inhibitor, showed single-agent antitumor activity in mCRPC. In the phase 1b/2 KEYNOTE-365 study (NCT02861573), docetaxel + pembro and prednisone showed activity in pts treated with abi or enza for mCRPC, warranting further evaluation. Methods: KEYNOTE-921 (NCT03834506) is a phase 3 trial to evaluate efficacy and safety of pembro + docetaxel and prednisone in chemotherapy-naive pts who progressed with enza or abi therapy for mCRPC. An estimated 1000 pts will be randomly assigned 1:1 to receive docetaxel 75 mg/m2 IV every 3 weeks (Q3W) + prednisone/prednisolone orally 5 mg twice daily (BID) and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID + placebo IV Q3W. Treatment will be stratified by previous next-generation hormone agent (abi or enza) and metastases location (bone only, liver, other). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who progressed with androgen deprivation therapy (or postbilateral orchiectomy) ≤6 months of screening, have ECOG PS 0 or 1, and have adequate organ function are eligible. Pts must have experienced either progression after ≥8 weeks (≥14 weeks for bone progression) or intolerance after ≥4 weeks of abi or enza (but not both) in a chemotherapy-naive mCRPC state. Pts will be required to provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment will continue with docetaxel and prednisone for up to 10 cycles and with pembro for up to 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are rPFS by BICR and OS. Secondary end points are time to initiation of subsequent anticancer therapy or death, PSA response rate, time to PSA progression, ORR and DOR per PCWG3-modified RECIST v1.1 assessed by BICR, and safety. Accrual began May 2, 2019. Clinical trial information: NCT03834506.

Phase III study of pembrolizumab (pembro) plus olaparib versus enzalutamide (enza) or abiraterone acetate (abi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who progressed on chemotherapy: KEYLYNK-010.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS256-TPS256 ◽  
Author(s):  
Evan Y. Yu ◽  
Se Hoon Park ◽  
Yi-Hsiu Huang ◽  
Mostefa Bennamoun ◽  
Lu Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
End Points ◽  
Investigation Methods ◽  
Biomarker Analysis ◽  
Modified Recist

TPS256 Background: Pembro, a PD-1 inhibitor, and olaparib, a PARP inhibitor, have some single-agent antitumor activity in mCRPC. The phase 1b/2 KEYNOTE-365 study (NCT02861573) showed promising activity with pembro and olaparib in pts with mCRPC unselected for homologous recombination deficiency, warranting further investigation. Methods: KEYLYNK-010 (NCT03834519) is a phase 3 trial to evaluate efficacy and safety of pembro + olaparib in molecularly unselected enza- or abi-pretreated pts with mCRPC who progressed with taxane chemotherapy. An estimated 780 pts will be randomly assigned 2:1 to receive pembro 200 mg IV every 3 wk plus olaparib 300 mg orally twice daily or abi 1000 mg orally once daily + prednisone/prednisolone 5 mg orally twice daily (enza-pretreated pts) or enza 160 mg/day orally (abi-pretreated pts). Stratification will be by prior treatment (abi/enza) and measurable disease (yes/no). Adults (≥18 y) with histologically confirmed mCRPC who progressed on androgen deprivation therapy ≤6 mo of screening, and an ECOG PS of 0 or 1 are eligible. Pts previously received either abi or enza (but not both) as well as 1 docetaxel-based regimen. Pts are required to provide tumor tissue for biomarker analysis. Responses will be assessed by CT/MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 9 wk during the first year and every 12 wk thereafter. Treatment will continue with up to 2 y of pembro (35 cycles) and olaparib or abi/enza until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are OS and rPFS. Secondary end points are time to initiation of subsequent anticancer therapy; ORR, and DOR per PCWG3-modified RECIST v1.1 by BICR; time to PSA progression; time to first symptomatic skeletal event; time to radiographic soft tissue progression; time to pain progression; and safety. Exploratory end points are identification of molecular (genomic, metabolic, or proteomic) biomarkers indicative of response. Accrual began May 2, 2019. Clinical trial information: NCT03834519.

Pembrolizumab (pembro) plus enzalutamide (enza) in patients (pts) with abiraterone acetate (abi)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort C efficacy, safety, and biomarker results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5545-5545 ◽  
Author(s):  
Henry Jacob Conter ◽  
Neal D. Shore ◽  
William R. Berry ◽  
Peter C.C. Fong ◽  
Jose Maria M. Piulats Rodriguez ◽  
...  
Keyword(s):  
Response Rate ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
End Points ◽  
Biomarker Analysis ◽  
Measurable Disease ◽  
Psa Response ◽  
Combined Positive Score

5545 Background: Pembro + enza (cohort C) has shown antitumor activity and acceptable safety in abi-pretreated pts with mCRPC in the phase I/II KEYNOTE-365 study (NCT02861573). Updated results with new biomarker data from cohort C are reported. Methods: Pts who became intolerant to or for whom ≥4 weeks of abi failed in the prechemotherapy mCRPC state and who progressed within 6 mo of screening were enrolled. Pts received pembro 200 mg IV Q3W + enza 160 mg/day orally. Primary end points were PSA response rate (PSA decrease ≥50%; confirmed by a second value ≥3 weeks later), ORR per RECIST v1.1 by blinded independent central review, and safety. Key secondary end points were DCR per RECIST v1.1 (CR+PR+SD or non-CR/non-PD ≥6 mo), DOR per RECIST v1.1, radiographic PFS (rPFS) per PCWG-modified RECIST v1.1, and OS. Biospecimens (eg, blood, tissue) were collected at baseline and during the study for biomarker analysis, including tissue PD-L1 expression, androgen receptor variant 7 (AR-v7) expression in circulating tumor cells (CTCs), and a T-cell-inflamed gene expression profile (GEP). Results: Of 103 enrolled pts, 102 were treated; 39% of treated pts had measurable disease. Median (range) time from enrollment to data cutoff was 19.1 mo (1.1-28.8) for all pts and 21.4 mo (15.1-28.8) for pts with ≥27 wks’ follow-up (n=69). Confirmed PSA response rate was 22% in 101 pts with a baseline PSA assessment. Median time to PSA progression was 3.5 mo (95% CI, 2.9-4.0). In pts with measurable disease and ≥27 wks’ follow-up (n=25), confirmed ORR was 12% (2 CRs, 1 PR) and DCR was 32%. Median DOR was not reached (range, 0.0+ to 24.4+ mo); 2 pts had a response for ≥6 mo. In all pts, median (95% CI) rPFS was 6.1 mo (4.4-6.5) and median OS was 20.4 mo (15.5-NR). At 6 mo, rPFS rate was 55.1% and OS rate was 88.2%. Treatment-related AEs occurred in 92 pts (90%); most frequent (≥20%) were fatigue (38%), nausea (22%), and rash (20%). Grade 3-5 treatment-related AEs occurred in 40 pts (39%). Three pts died of AEs (1 AE was treatment related [cause unknown]). Of all pts, 29% had PD-L1+ tumors (combined positive score ≥1). Of 51 pts with AR-v7 data, 13.7% were AR-v7+ and 86.3% were AR-v7−. GEP was not significantly associated with ORR or PSA response. Conclusions: Pembro + enza continued to show activity in pts with abi-pretreated mCRPC. Safety of the combination was consistent with the known profiles of pembro and enza. A phase III study of this combination is ongoing (KEYNOTE-641, NCT03834493). Clinical trial information: NCT02861573 .

Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) versus placebo plus enza for metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-641.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS258-TPS258 ◽  
Author(s):  
Julie Nicole Graff ◽  
Joseph Burgents ◽  
Li Wen Liang ◽  
Arnulf Stenzl
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Placebo Treatment ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
End Points ◽  
Biomarker Analysis ◽  
Receptor Inhibitor

TPS258 Background: The mechanisms of action of pembro, a PD-1 inhibitor, and enza, an androgen receptor inhibitor, may be synergistic in the treatment of patients (pts) with mCRPC. The phase 1b/2 KEYNOTE-365 (NCT02861573) study showed antitumor activity with pembro + enza in pts with mCRPC pretreated with abiraterone acetate. A phase 2 study (NCT02312557) of enza-pretreated patients with mCRPC showed that some pts had a profound and durable anticancer response to pembro + enza. Methods: KEYNOTE-641 (NCT03834493) is a randomized, double-blind, phase 3 trial to evaluate efficacy and safety of pembro + enza versus placebo + enza in pts with mCRPC. An estimated 1200 patients will be randomly assigned 1:1 to receive enza 160 mg/day + pembro 200 mg IV Q3W or enza 160 mg/day + placebo. Treatment will be stratified by prior abiraterone acetate treatment (yes/no), metastases location (bone only/liver/other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes/no). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who experienced biochemical or radiographic progression, ECOG PS 0/1, and adequate organ function are eligible. Pts will be required to provide tissue for biomarker analysis. Intolerance to or progression while receiving prior abiraterone acetate therapy is permitted, but not required. Prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor is prohibited. Responses will be assessed by CT/MRI and radionuclide bone imaging per PCWG3-modified RECIST v1.1 Q9W during the first year and Q12W thereafter. Treatment will continue until progression, unacceptable toxicity, or consent withdrawal, with up to 2 years of pembro/placebo. Dual primary end points are OS and rPFS by blinded independent central review. Secondary end points are time to subsequent anticancer therapy or death, ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to soft tissue progression, time to symptomatic skeletal-related event, and safety. Accrual began July 28, 2019. Clinical trial information: NCT03834493.

Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): KEYNOTE-991.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5595-TPS5595
Author(s):  
Christian Gratzke ◽  
Joseph E Burgents ◽  
Cuizhen Niu ◽  
Christian Heinrich Poehlein ◽  
Charles G. Drake
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Response Rate ◽  
Phase Iii ◽  
Antitumor Effects ◽  
End Points ◽  
Once Daily ◽  
Patient Reported ◽  
Biomarker Analysis ◽  
Modified Recist

TPS5595 Background: Pembro, an anti–PD-1 antibody, has shown antitumor activity as monotherapy and in combination with other agents in metastatic castration-resistant prostate cancer (mCRPC). As the antitumor effects of enza may be pro-immunogenic, we hypothesized that combining pembro and enza could show additive or synergistic antitumor activity. Furthermore, pembro + enza previously showed antitumor activity in pts with mCRPC for whom abiraterone failed (KEYNOTE-365, NCT02861573) and in pts with mCRPC for whom enza monotherapy failed (KEYNOTE 199, NCT02787005). These data warrant further evaluation of the combination of pembro + enza when given at the initiation of ADT. Methods: KEYNOTE-991 (NCT04191096) is a phase III trial to evaluate the efficacy and safety of enza + ADT + either pembro or placebo in patients with mHSPC. Approximately 1232 pts will be randomly assigned 1:1 to receive enza 160 mg orally once daily + ADT + pembro 200 mg IV every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. ADT is receipt of an LHRH agonist or antagonist during study treatment or bilateral orchiectomy. Treatment will be stratified by prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Pts with mHSPC, with ≥2 bone lesions and/or visceral disease, who are naive to next-generation hormone agents, and who have ECOG PS 0 or 1 are eligible. Pts must provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Treatment will continue with pembro for up to 35 cycles, and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. Dual primary end points are radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 assessed by BICR and overall survival. Secondary end points are time to first subsequent anticancer therapy, time to symptomatic skeletal-related event, PFS2 (progression after next line of therapy or death), prostate-specific antigen (PSA) response rate, time to PSA progression, PSA undetectable rate, objective response rate, duration of response, and time to radiographic soft tissue progression. Other end points are safety and patient-reported outcomes (eg, time to pain progression). Clinical trial information: NCT04191096 .

Pembrolizumab (pembro) plus docetaxel and prednisone in patients (pts) with abiraterone acetate (abi) or enzalutamide (enza)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort B efficacy, safety and, biomarker results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5550-5550
Author(s):  
Srikala S. Sridhar ◽  
Michael Paul Kolinsky ◽  
Gwenaelle Gravis ◽  
Loic Mourey ◽  
Jose Maria M. Piulats Rodriguez ◽  
...  
Keyword(s):  
Response Rate ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
End Points ◽  
Biomarker Analysis ◽  
Measurable Disease ◽  
Psa Response ◽  
Combined Positive Score ◽  
The Individual

5550 Background: Pembro + docetaxel and prednisone (cohort B) has shown antitumor activity in pts with mCRPC in the phase I/II KEYNOTE-365 study (NCT02861573). Updated efficacy and safety and new biomarker data from cohort B are reported. Methods: Pts who received at least 4 wk of abi or enza in the prechemotherapy mCRPC setting and whose disease progressed within 6 mo of screening were eligible. Pts received pembro 200 mg IV + docetaxel 75 mg/m2 IV Q3W and prednisone 5 mg orally twice daily. Primary end points were PSA response rate (PSA decrease ≥50%; confirmed by a second value ≥3 weeks later), ORR per RECIST v1.1 by blinded independent central review, and safety. Key secondary end points were DCR per RECIST v1.1 (CR+PR+SD or non-CR/non-PD ≥6 mo), DOR per RECIST v1.1, radiographic PFS (rPFS) per PCWG-modified RECIST, and OS. Biospecimens (blood, tissue) were collected for biomarker analysis, including tissue PD-L1 expression, androgen receptor variant 7 (AR-v7) expression in circulating tumor cells, and a T-cell-inflamed gene expression profile (GEP). Results: Of 105 enrolled pts, 104 were treated, and 50% had measurable disease. Median (range) time from enrollment to data cutoff was 19.9 mo (1.4-27.8) for all pts and 21.8 mo (17.9-27.8) for pts with ≥27 wks follow-up (n=72). Confirmed PSA response rate was 28% in 103 pts with a baseline PSA assessment. Median time to PSA progression was 6.2 mo (95% CI, 3.7-7.4). In pts with measurable disease and ≥27 wks follow-up (n=39), ORR was 18% (7/39, all PRs) and DCR was 51%. Median DOR was 6.7 mo (range, 3.4-9.0+ [+ indicates ongoing responder]); 5 pts had a response for ≥6 mo. In all pts, median rPFS was 8.3 mo (95% CI, 7.6-10.1) and OS was 20.4 mo (16.9-NR). At 6 mo, the rPFS rate was 72.8% and OS rate was 95.3%. Treatment-related AEs (TRAEs) occurred in 96% of all pts; most frequent were alopecia (39%), diarrhea (38%), and fatigue (38%). Grade 3-5 TRAEs occurred in 40% of pts; 2 pts died of TRAEs (pneumonitis). Overall, 24% of pts were PD-L1+ (combined positive score ≥1). Of 57 pts with AR-v7 data, 17.5% were AR-v7+, 77% were AR-v7−, and 5% were undetermined. GEP was not significantly associated with ORR or PSA response. Conclusions: Pembro + docetaxel and prednisone showed activity in pts with abi or enza-pretreated mCRPC. Safety of the combination was consistent with the known profiles of the individual agents. A phase 3 study of this combination is ongoing (KEYNOTE-921, NCT03834506). Clinical trial information: NCT02861573 .

343 Phase 3 study of pembrolizumab + docetaxel and prednisone/prednisolone for metastatic castration-resistant prostate cancer (mCRPC) pretreated with next-generation hormonal agents (NHAs) (KEYNOTE-921)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A368-A368
Author(s):  
Daniel Petrylak ◽  
Neal Shore ◽  
Mostefa Bennamoun ◽  
Raffaele Ratta ◽  
Josep Piulats ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Response Rate ◽  
Abiraterone Acetate ◽  
Prior Treatment ◽  
Phase 3 ◽  
End Points ◽  
Link Type ◽  
Psa Response ◽  
Modified Recist

BackgroundCohort B of the phase 1b/2 KEYNOTE-365 study (NCT02861573) found that docetaxel + pembrolizumab + prednisone demonstrated activity in patients previously treated with abiraterone acetate or enzalutamide for mCRPC. The prostate-specific antigen (PSA) response rate was 28%; objective response rate (ORR) was 18% (7 partial responses); duration of response (DOR) was 6.7 months; progression-free survival (PFS) was 8.3 months; overall survival (OS) was 20.4 months; and the 12-month PFS and OS rates were 24.0% and 75.8%, respectively. The safety and tolerability profile of this combination was consistent with the profiles of each individual agent. The KEYNOTE-921 (NCT03834506) phase 3 trial will evaluate efficacy and safety of pembrolizumab + docetaxel + prednisone/prednisolone in patients with mCRPC after prior treatment with NHA.MethodsEligible patients are adults with histologically or cytologically confirmed mCRPC who experience disease progression with androgen deprivation therapy (or after bilateral orchiectomy) within 6 months of screening and have Eastern Cooperative Oncology Group performance status 0/1. Other eligibility criteria are disease progression or intolerance to NHA in the metastatic hormone-sensitive prostate cancer setting or CRPC setting, no prior treatment with chemotherapy for mCRPC, and tissue available for biomarker analysis. Treatment stratification factors are prior treatment with abiraterone acetate (yes or no) and metastases location (bone only, liver, other). Approximately 1000 patients will be randomly assigned to receive docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg PO BID + placebo IV Q3W (1:1 ratio). Response and progression will be determined using imaging (CT/MRI/bone) according to PCWG3–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment maximums are 10 cycles for docetaxel + prednisone/prednisolone and 35 cycles for pembrolizumab or placebo. Treatment discontinuation regardless of therapy received is mandated for disease progression, unacceptable toxicity, or consent withdrawal. The dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by BICR and OS, and the key secondary end point is time to initiation of subsequent anticancer therapy or death. Other secondary end points include PSA response rate, time to PSA progression, ORR, DOR, time to radiographic soft tissue progression, time to radiographic bone progression, and safety. KEYNOTE-921 is ongoing or planned in 22 countries across, Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/AEthics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5047-5047
Author(s):  
A. H. Reid ◽  
G. Attard ◽  
D. Danila ◽  
C. J. Ryan ◽  
E. Thompson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Patient Demographics ◽  
Castration Resistant ◽  
Heavily Pretreated ◽  
Key Enzyme ◽  
Psa Response ◽  
Docetaxel Chemotherapy

5047 Background: Despite castration, androgens remain critical to prostate cancer. Abiraterone acetate (AA) specifically and irreversibly inhibits CYP17, a key enzyme in androgen biosynthesis. Methods: 47 CRPC pts who had failed androgen deprivation therapy and had prior docetaxel chemotherapy received AA orally (1000mg QD) in 28 day cycles. Low dose glucocorticoids were allowed. Results: Patient demographics in table . Total maximal PSA declines with AA at any point on study of ≥30%, ≥50%, and ≥ 90% were observed in 32 (69%), 24 (51%) and 7 (15%) pts respectively. A similar trend in PSA response was seen at wk 12. 35 pts were evaluable by RECIST; 6 (17%) pts had a partial response and 23 (66%) pts had stable disease. 23% of pts showed ECOG improvement (PS 1 to 0 in 10 pts, PS 2 to 1 in 1 pt); 53% of pts maintained PS. Median duration on treatment was 167 days (95% CI 130–201). 17 pts received >6 cycles of AA; 8 pts received ≥ 12 cycles. Toxicities related to mineralocorticoid excess were mainly grade 1–2 (hypokalemia 51%; HTN 17%; edema 13%) and were treated with eplerenone or corticosteroids. Conclusions: AA has anti-tumor activity in these heavily pretreated pts, as evidenced by sustained PSA declines, improvement in PS and RECIST responses. A phase III trial assessing the efficacy and safety of AA and prednisone in CRPC pts who have failed docetaxel chemotherapy is underway. [Table: see text] [Table: see text]

Androgen Receptor Rediscovered: The New Biology and Targeting the Androgen Receptor Therapeutically

2011 ◽  
Vol 29 (27) ◽  
pp. 3651-3658 ◽  
Author(s):  
Charles J. Ryan ◽  
Donald J. Tindall
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Clinical Success ◽  
Abiraterone Acetate ◽  
Clinical Findings ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant

Discoveries over the past decade suggest that castration-resistant prostate cancer (CRPC) is sensitive, but not resistant to, further manipulation of the androgen–androgen receptor (AR) axis. Several new therapies that target this axis have demonstrated clinical activity. In this article, preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed. Reviews of scientific and clinical development are divided into those occurring prereceptor (androgen production and conversion) and at the level of the receptor (AR aberrations and therapies targeting AR directly). Intracrine androgen production and AR amplification, among others, are among the principal aberrancies driving CRPC growth. Phase III data with abiraterone acetate and phase II data with MDV-3100, along with other similar therapies, confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease. Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way. The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling, even in the castrate state.

Novel therapies and emerging strategies for the treatment of patients with castration-resistant prostate cancer

2017 ◽  
Author(s):  
Deborah Mukherji ◽  
Aurelius Omlin ◽  
Carmel Pezaro ◽  
Johann De Bono
Keyword(s):  
Prostate Cancer ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Trial Participation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Radium 223 ◽  
New Treatments ◽  
Phase Iii Studies ◽  
Clinical And Translational Research

Castration-resistant prostate cancer (CRPC) represents a final stage of this malignancy for many men and is defined as the progression of prostate cancer despite castrate levels of testosterone. CRPC may present as a rising PSA, the development of new metastases, or worsening of known metastases. Recent advances have resulted in five new treatments for CRPC: the immunotherapy sipuleucel-T; the cytotoxic cabazitaxel; the androgen biosynthesis inhibitor abiraterone acetate; the radioisotope radium-223; and the antiandrogen enzalutamide. These have all improved overall survival in randomized phase III studies for patients with metastatic CRPC. Furthermore, multiple agents and combinations are currently in late-stage clinical testing. Men with advanced prostate cancer represent an important population for clinical and translational research and clinical trial participation should be considered as part of standard care.

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