A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer and advanced/recurrent endometrial cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2663-TPS2663
Author(s):  
Raanan Alter ◽  
Gini F. Fleming ◽  
Walter Michael Stadler ◽  
Akash Patnaik
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Combination Therapy ◽  
Parp Inhibitor ◽  
Primary Objective ◽  
Parp Inhibition ◽  
Wide Range ◽  
Castrate Resistant Prostate Cancer ◽  
Endometrial Cancers ◽  
Castrate Resistant

TPS2663 Background: Immune checkpoint blockade (ICB) antibodies have made a major impact in a wide range of cancers. However, only subsets of patients across all malignancies benefit from ICB. In particular, metastatic castrate-resistant prostate cancer (mCRPC) and advanced endometrial cancers (EC) have shown very limited responses to ICB. The central hypothesis of this trial is that the combination of PARP inhibitor (rucaparib) with PD-1 inhibitor (nivolumab) will enhance ICB efficacy in mCRPC and mEC patients. Given that PTEN loss has also been associated with poor response to ICB, a secondary hypothesis of this study is that the combination therapy will have differing efficacy based on the PTEN mutation status of the tumor. Methods: This is an investigator-initiated Phase 1b/IIa clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC and mEC patients. Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms will switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in immune infiltrates by Nanostring RNA sequencing, multiplex immunofluorescence, 3D mapping, IHC, and flow cytometry. Secondary objectives are to assess clinical response, and correlate changes in TME with PTEN status. We have currently enrolled 4 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study presents an opportunity for in-depth TME analysis that will enable the delineation of the effects of PARP inhibition singly and in combination with PD-1 blockade, on immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immunooncology combinations for specific molecular subsets of prostate and endometrial cancers. Clinical trial information: NCT03572478.

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

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2676 ◽  
Author(s):  
Sebastian Pölsterl ◽  
Pankaj Gupta ◽  
Lichao Wang ◽  
Sailesh Conjeti ◽  
Amin Katouzian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Survival Analysis ◽  
Ensemble Methods ◽  
Phase Iii ◽  
Survival Models ◽  
Phase Iii Clinical Trials ◽  
Wide Range ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Heterogeneous Ensemble

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

A phase Ib/II study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer (NCT03431350).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5087-TPS5087 ◽  
Author(s):  
Sumit Kumar Subudhi ◽  
Ana Aparicio ◽  
Amado J. Zurita ◽  
Bernard Doger ◽  
William Kevin Kelly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Parp Inhibitor ◽  
Rapid Identification ◽  
Abiraterone Acetate ◽  
Parp Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Abstract Submission

TPS5087 Background: Assessing multiple therapies in a single clinical trial can facilitate the rapid identification of new agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib (Nirap) is a highly selective PARP inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. PARP inhibition may be especially lethal in tumor cells with genetic DNA damage response deficits (DRD). Based on promising preclinical and clinical data, this study is designed as a master protocol with nirap as a backbone therapy. Combination 1 assesses the safety and efficacy of nirap plus JNJ-63723283 (JNJ-283), an anti-PD-1 monoclonal antibody. Combination 2 assesses nirap plus abiraterone acetate and prednisone (AA-P). Methods: This multicenter, global, open-label study is currently open at 18 sites in 5 countries of the planned XX sites, and is enrolling patients with mCRPC who have progressed on ≥1 androgen-receptor targeted therapy for mCRPC. Enrollment at time of abstract submission was 25 for combination 1. When combined with AA-P, the RP2D has been determined to be nirap 200 mg. The recommended phase-2 dose (RP2D) of nirap plus JNJ-283 was determined in Part 1 based on the incidence of specified adverse events and PK data to be 480 mg every 4 weeks. For Part 2 of the study, patients are assigned to receive oral niraparib daily plus JNJ-283 infusions once every four weeks until disease progression, unacceptable toxicity, death, study termination. Part 2 is described in the table. Clinical trial information: NCT03431350. [Table: see text]

Overall survival after 177Lu-PSMA-617 molecular radiotherapy in patients with metastatic castrate-resistant prostate cancer: Post-hoc analysis of a prospective phase II trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5549-5549 ◽  
Author(s):  
Jeremie Calais ◽  
Jeannine Gartmann ◽  
Wesley R Armstrong ◽  
Pan Thin ◽  
Kathleen Nguyen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Post Hoc Analysis ◽  
Molecular Radiotherapy ◽  
Prospective Phase ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Post Hoc

5549 Background: This was an open-label randomized prospective bi-centric single-arm phase II clinical trial of 177Lu-PSMA-617 molecular radiotherapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC) conducted at University of California Los Angeles (USA) and Excel Diagnostics & Nuclear Oncology Center (Houston, TX, USA) (NCT03042312). The study was investigator-initiated under an investigational new drug approval protocol (IND#133661) with authorization of charging for investigational drug (cost-recovery, Title 21 CFR 312.8). We report here the post-hoc analysis of overall survival (OS) in a single-study site cohort (UCLA). Methods: Patients with progressive mCRPC (biochemical, radiographic, or clinical) after ≥1 novel androgen axis drug (NAAD), either chemotherapy (CTX) naïve or post-CTX, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA-target expression by PET were eligible. Patients received up to 4 cycles of 177Lu-PSMA-617 every 8±1 weeks and were randomized into 2 treatment activities groups (6.0 or 7.4 GBq). Efficacy was defined as serum PSA decline of ≥50% from baseline and served as primary endpoint (hypothesis: ≥40% of responders after 2 cycles). Results: 43 patients were randomized to the 6.0 GBq (n= 14) and 7.4 GBq (n=29) treatment arms. 11/43 (26%) were CTX naïve while 10/43 (23%), 12/43 (28%), 5/43 (12%) and 5/43 (12%) had received 1, 2, 3 or 4 CTX regimens. Median baseline PSA was 29.2 ng/ml (mean 228.8, range 0.5-2082.6). 21/43 (49%) completed 4 cycles of 177Lu-PSMA-617 whereas 4/43 (9%), 13/43 (30%) and 5/43 (12%) underwent 1, 2 and 3 cycles. PSA decline of ≥50% was observed in 11/43 of patients (26%) after 2 cycles and in 16/43 (37%) at any time (best PSA response). 9/43 (21%) had a PSA decline of ≥90% and 23/43 (53%) had any PSA decline (>0%). After a median follow-up of 19.5 months the median OS was 14.8, 15.7 and 13.5 months in the whole cohort, the 6.0 GBq and 7.4 GBq treatment arms, respectively (p=0.68). Patients showing a PSA decline of ≥50% after 2 cycles and at any time had a longer OS: median 20.1 months vs. 13.6 (p=0.091) and 20.1 vs. 11.6 (p=0.002), respectively. Conclusions: In this post-hoc analysis of a single-site cohort of 43 patients included in a prospective phase II trial the median OS after 177Lu-PSMA-617 molecular radiotherapy in patients with progressive mCRPC was 14.8 months. There was no difference of efficacy between the 6.0 GBq and 7.4 GBq treatment arms. Clinical trial information: NCT03042312 .

A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS270-TPS270
Author(s):  
Akash Patnaik ◽  
Priyanka Duttagupta ◽  
Kiranj Chaudagar ◽  
Raanan Alter ◽  
Hanna Hieromnimon ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Predictive Biomarkers ◽  
Cell Infiltration ◽  
Parp Inhibition ◽  
Rna Seq ◽  
Phase Ib ◽  
Wide Range ◽  
Castrate Resistant ◽  
The Impact

TPS270 Background: Immune checkpoint blockade (ICB) therapies have had a major impact across a wide range of cancers. However, only subsets of patients across all malignancies benefit from ICB. In particular, metastatic castrate-resistant prostate cancers (mCRPC) have shown very limited responses to ICB. While there is ongoing work to identify predictive biomarkers to ICB responsiveness, early preclinical data from our group suggests that targeting fundamental DNA repair pathways could markedly increase the fraction of patients responsive to immunotherapeutic interventions. Based on these preclinical studies, we are conducting an investigator-initiated Phase Ib/IIa co-clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC patients. Methods: Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in T cell infiltration by RNA-seq analysis using established T-cell non-inflamed and inflamed gene signatures. Secondary objectives are to assess changes in immune cell infiltration via flow cytometry, multiplex IHC, transparent tissue tomography (3D mapping) and single-cell RNA-seq. We will correlate changes in the metastatic tumor microenvironment (TME) at baseline and following 4 weeks of treatment, with genomic alterations and clinical responses. We have currently enrolled 12 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study utilizes novel emerging technologies for in-depth TME analysis that will unravel the impact of PARP inhibition, singly and in combination with PD-1 blockade, on specific immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immuno-oncology combinations for specific genomic subsets of mCRPC. Clinical trial information: NCT03572478.

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

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2676 ◽  
Author(s):  
Sebastian Pölsterl ◽  
Pankaj Gupta ◽  
Lichao Wang ◽  
Sailesh Conjeti ◽  
Amin Katouzian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Survival Analysis ◽  
Ensemble Methods ◽  
Phase Iii ◽  
Survival Models ◽  
Phase Iii Clinical Trials ◽  
Wide Range ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Heterogeneous Ensemble

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

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

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2676 ◽  
Author(s):  
Sebastian Pölsterl ◽  
Pankaj Gupta ◽  
Lichao Wang ◽  
Sailesh Conjeti ◽  
Amin Katouzian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Survival Analysis ◽  
Ensemble Methods ◽  
Phase Iii ◽  
Survival Models ◽  
Phase Iii Clinical Trials ◽  
Wide Range ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Heterogeneous Ensemble

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

CX-5461 sensitises DNA damage repair proficient castrate-resistant prostate cancer to PARP inhibition

2021 ◽  
pp. molcanther.0932.2020
Author(s):  
Mitchell G Lawrence ◽  
Laura H Porter ◽  
Nicholas Choo ◽  
David Pook ◽  
Jeremy P Grummet ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Parp Inhibition ◽  
Damage Repair ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Olaparib for the treatment of metastatic prostate cancer

2021 ◽  
Author(s):  
Corinne Maurice Dror ◽  
Alexander W Wyatt ◽  
Kim N Chi
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Metastatic Prostate Cancer ◽  
Additional Treatment ◽  
Parp Inhibition ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Molecular Landscape

Recent innovations in the treatment of metastatic prostate cancer have improved patient outcomes. Nonetheless, this disease remains fatal and additional treatment approaches are needed. Greater understanding of the molecular landscape of metastatic prostate cancer has revealed recurrent alterations in key pathways amenable to therapeutic targeting. One such pathway is DNA repair, particularly alterations in genes directly or indirectly associated with homologous recombination repair found in up to one-quarter of patients with metastatic castrate-resistant prostate cancer (mCRPC). Olaparib, an inhibitor of poly-ADP-ribose polymerase, has recently gained approval for the treatment of mCRPC harboring alterations in homologous recombination repair genes. This review will provide a summary of evidence regarding PARP inhibition in the treatment of mCRPC, with a specific focus on olaparib.

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