NGS, RNA-Seq, TIL, and PTEN analyses in prostate cancer specimens from patients enrolled in the study of the Akt inhibitor ipatasertib (Ipat) combined with abiraterone acetate (AA).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 310-310
Author(s):  
Liangxuan Zhang ◽  
Hartmut Koeppen ◽  
Daniel J. Maslyar ◽  
Dimitri Fillos ◽  
Na Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Checkpoint Inhibitors ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Immune Checkpoints ◽  
Rna Seq ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Pten Loss ◽  
High Level

310 Background: In Phase III studies, ipilimumab did not extend OS in unselected populations with metastatic castration-resistant prostate cancer (mCRPC) (Kwon, 2014; Beer, 2014), suggesting that successful cancer immunotherapy development strategies require the evaluation of treatment effects in biomarker-driven segments. In addition, PTEN loss has been identified as a potential mechanism of resistance to immunotherapy (Peng, 2016). Therefore, we explored possible associations between cancer immunity (CI)-related biomarkers and PTEN loss in mCRPC samples. Methods: Tumor samples obtained in the Phase II study of AA ± Ipat in patients with mCRPC (de Bono, ESMO 2016) were retrospectively profiled. DNA alterations and tumor mutational burden (TMB) were assessed by FoundationOne. RNA-seq analysis of multiple CI-related expression signatures was performed. Tumor-immune lymphocyte (TIL) scores were analyzed in 3 compartments (stromal, sTIL; intratumoral, iTIL; peritumoral, pTIL) based on H&E stained specimens. Up to 10 evenly distributed fields were examined; the average of these fields was used to estimate the %TILs for each compartment. Results: Strong associations were observed between multiple CI-related signatures (e.g., INFγ-induced, immune checkpoints, Treg, checkpoint inhibitors). Fewer than 10% of the samples had a high level (≥ 10% of the tumor area) of TIL infiltration in any compartment (Table). TIL scores, TMB values, PTEN status and Gleason score all appeared to be independently associated, and none were associated with CI-related gene signatures, except for a possible association between pTILs and the B-cell signature (ρ = 0.49, P < 0.0001). Conclusions: Comprehensive high-content profiling of prostate cancer samples suggests that PTEN status and CI-related biomarkers were independently associated, while TMB and TIL values were generally not associated with CI-related signatures. Clinical trial information: NCT01485861. [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.

Recent Developments in Treatments for Metastatic Castration-resistant Prostate Cancer—A Mechanistic Perspective

2012 ◽  
Vol 08 (02) ◽  
pp. 89
Author(s):  
Guru Sonpavde ◽  
E David Crawford ◽  
◽  
Keyword(s):  
Prostate Cancer ◽  
Abiraterone Acetate ◽  
Chemotherapeutic Agents ◽  
New Drugs ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Microtubule Inhibitor ◽  
Phase Iii Clinical Trials ◽  
Castration Resistant ◽  
Radium 223

Over the past decade, the treatment landscape in metastatic castration-resistant prostate cancer (CRPC) has markedly changed, with the introduction of three new chemotherapeutic agents. The mechanism of CRPC is not fully understood, but it may result from multiple pathways, including a loss or androgen receptor (AR) specificity and increased downstream signalling activity that provide multiple targets for therapeutic agents. For some years, docetaxel was the mainstay of treatment in CRPC, but recently, cabazitaxel (a microtubule inhibitor), sipuleucel-T (a cancer vaccine), and abiraterone acetate (a CYP17 inhibitor) were approved for CRPC treatment. In Phase III clinical trials, these agents have shown significant improvements in survival—over mitoxantrone (for cabazitaxel) and over placebo (for sipuleucel-T and abiraterone acetate)—and were well tolerated. There are also two treatments in late-stage development, MDV3100 (an oral AR antagonist) and radium-223 (an isotope that creates breaks in double-stranded DNA). These have also shown improvements in survival in Phase III trials; their regulatory approval is expected soon. The modes of actions of the existing and new drugs in CRPC are varied, but some are complementary and investigations of different combinations of these medications are much needed; they may enhance efficacy, further extend survival, and improve outcomes in this formerly untreatable disease.

Targeting reciprocal feedback inhibition: Apalutamide and everolimus in patients with metastatic castration-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 204-204 ◽  
Author(s):  
Dana E. Rathkopf ◽  
Susan F. Slovin ◽  
Michael J. Morris ◽  
Daniel Costin Danila ◽  
Anthony Delacruz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Historical Data ◽  
Feedback Inhibition ◽  
Phase 1 ◽  
Mtor Inhibitors ◽  
Pi3k Pathway ◽  
Abiraterone Acetate ◽  
Fixed Dose ◽  
Castration Resistant Prostate Cancer ◽  
Pten Loss

204 Background: Studies in xenograft CRPC and PTEN-deficient prostate cancer models have shown synergistic anti-tumor activity of next-generation anti-androgens such as apalutamide when combined with PI3K/mTOR inhibitors such as everolimus. (Carver B et al., Cancer Cell 2011) The primary hypothesis of this study was that the combination of apalutamide with everolimus would overcome resistance to prior hormonal therapy with abiraterone acetate and prednisone (AAP). Methods: The primary endpoint in mCRPC patients with prior AAP was to evaluate the safety, pharmacokinetics (PK), and recommended phase 2 dose (RP2D) of fixed dose apalutamide 240 mg po qd when combined with everolimus 5 mg po qd (cohort 1, n = 3) and everolimus 10 mg po qd (cohort 2, n = 6). The plan was to expand to treat 40 patients at the RP2D. Results: Nine patients were enrolled in phase 1. The PK for the combination was consistent with historical data of either drug given as monotherapy. The most common treatment related adverse events were < = grade 2 fatigue (67%), diarrhea (56%), and anorexia (56%). In cohort 2, 1 patient had a DLT of grade 3 rash. The median time on treatment was 17 weeks (range 7-51+). The best response was SD in all 9 patients. Patients came off study for: progression (n = 3), investigator choice (n = 3) and toxicity unrelated to treatment (n = 2). Seven patients had detectable CTCs at baseline (EPIC Sciences). One patient had a rise in CTC number that then converted to undetectable and remained on study 37 weeks. One out of 6 evaluable patients had PTEN loss in tissue at baseline (MSK IMPACT) and remained on study 12 weeks. One patient with prior AAP and enzalutamide exposure has remained on study 51+ weeks with a > 50% decline in PSA (PTEN pending). Conclusions: Although the combination of apalutamide and everolimus was safe and well tolerated, the treatment response was similar to historical data of AAP followed by apalutamide alone. (Rathkopf D et al., ASCO 2014) We elected to close this study before expansion in favor of evaluating novel AR/PI3K pathway combinations in patients who have not yet been exposed to AAP. Drug provided by Janssen and Novartis. Trial support: PCF and MSK Experimental Therapeutics Center. Clinical trial information: NCT02106507.

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.

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.

scholarly journals KEYNOTE-921: Phase III study of pembrolizumab plus docetaxel for metastatic castration-resistant prostate cancer

2021 ◽  
Author(s):  
Daniel P Petrylak ◽  
Raffaele Ratta ◽  
Rustem Gafanov ◽  
Gaetano Facchini ◽  
Josep M Piulats ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Options ◽  
Unmet Need ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Clinical Trial Registration ◽  
Castration Resistant ◽  
Previously Treated

Despite recent advances, treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after next-generation hormonal agents (NHAs) are limited and provide only modest survival benefit. Thus, an unmet need remains for mCRPC patients after treatment with targeted endocrine therapy or NHA therapy. Pembrolizumab, a humanized monoclonal antibody for PD-1, has been found to have activity as monotherapy in patients with mCRPC and as combination therapy in a Phase Ib/II study with docetaxel and prednisone/prednisolone for patients previously treated with enzalutamide or abiraterone acetate. The aim of the randomized, double-blind, Phase III KEYNOTE-921 study is to evaluate the efficacy and safety of pembrolizumab plus docetaxel in patients with mCRPC who were previously treated with an NHA. Clinical trial registration: NCT03834506 ( ClinicalTrials.gov )

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