Second interim analysis (IA2) results from a phase II trial of TAK-385, an oral GnRH antagonist, in prostate cancer patients (pts).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 200-200 ◽  
Author(s):  
Fred Saad ◽  
James L. Bailen ◽  
Christopher Michael Pieczonka ◽  
Daniel R. Saltzstein ◽  
Paul R. Sieber ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gnrh Antagonist ◽  
Phase 1 ◽  
Specific Antigen ◽  
Phase 2 ◽  
Open Label ◽  
Gnrh Antagonists ◽  
Parallel Group ◽  
Hot Flush ◽  
Secondary Endpoints

200 Background: Gonadotropin-releasing hormone (GnRH) antagonists achieve rapid decrease in testosterone (T) without transient T surge seen with GnRH agonists and thus may avoid clinical flare symptomatology. TAK-385 is an investigational, oral, non-peptide GnRH antagonist highly selective for the human GnRH receptor (IC50 0.12 nM). We report IA2 results from a phase 2, randomized, open label, parallel group study of TAK-385 in pts with advanced prostate cancer (NCT02083185). Methods: Pts aged ≥ 18 yrs with histologically confirmed prostate cancer, baseline T > 150 ng/dL and prostate-specific antigen (PSA) > 2 ng/mL, who were candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, once daily (QD) or leuprorelin (LEU) 22.5 mg subcutaneously every 12 wks, for 48 wks. The primary endpoint was effective castration rate of TAK-385 (T < 50 ng/dL) from wk 5–24. Secondary endpoints included: safety, pharmacokinetics (PK), and PSA. Results: At data cut-off, 75 pts had received TAK-385 (39 at 80 mg, 36 at 120 mg QD); 20 pts received LEU. Median age was 73 yrs with TAK-385 and 68.5 yrs with LEU; median treatment duration was 35.1 wks and 37.8 wks. After 3 days/4 wks/24 wks of treatment, median T was 36.9/10.6/8.9 ng/dL with TAK385 vs 648.1/13.0/11.5 ng/dL with LEU. T < 50 ng/dL was sustained over 5–24 wks in 92% vs 95% of pts (TAK-385 vs LEU). After 24 wks, PSA was reduced by 97.3% to a median of 0.1 ng/mL with TAK-385 vs 92.4% to 0.2 ng/mL with LEU. All-grade adverse events occurred in 91% vs 95% of pts (TAK-385 vs LEU); the most common were hot flush (59/60%), fatigue (21/15%), elevated alanine aminotransferase (9/10%), nasopharyngitis (8/5%), and elevated aspartate aminotransferase (5/10%). Initial analysis of pooled phase 1/2 data showed similar PK in the phase 2 pts and in previously studied healthy men, with dose-proportional plasma trough levels over > 6 mos. Conclusions: At IA2, the efficacy of TAK-385 was consistent with the GnRH antagonist mechanism of action and the safety profile was good. TAK-385 rapidly reduced T and sustained castration ( < 50 ng/dL) over 24 wks. Further investigation of TAK-385, as an option to injectable GnRH therapies, is warranted. Clinical trial information: NCT02083185.

scholarly journals A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly

2018 ◽  
Vol 179 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Peter J Trainer ◽  
John D C Newell-Price ◽  
John Ayuk ◽  
Simon J B Aylwin ◽  
Aled Rees ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Human Growth ◽  
Phase 2 ◽  
Open Label ◽  
Parallel Group ◽  
Igf I ◽  
Secondary Endpoints ◽  
Efficacy Measures ◽  
Hormone Binding Protein ◽  
Antisense Oligonucleotide Therapy

Objective ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. Design Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. Methods The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Results and conclusions Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.

Safety of continued administration of enzalutamide in patients with prostate cancer who showed benefit from prior exposure: A phase 2 open-label extension study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 303-303
Author(s):  
Elaine Tat Lam ◽  
Russell Zelig Szmulewitz ◽  
Leonard Joseph Appleman ◽  
Anthony W. Tolcher ◽  
Andrew Krivoshik ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Laboratory ◽  
Hypertensive Crisis ◽  
Malignant Neoplasm ◽  
Extension Study ◽  
Phase 2 ◽  
Open Label ◽  
Hot Flush ◽  
Open Label Extension

303 Background: Enzalutamide (ENZA), an androgen receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway, is approved for patients (pts) with metastatic castration-resistant prostate cancer. This Phase 2, open-label, extension study (NCT01534052) evaluated long-term safety of continued ENZA administration. Methods: Prostate cancer pts previously treated with ENZA in Phase I studies (NCT01902251; NCT01911728; NCT02225093) continued to receive ENZA 160 mg/day until the investigator considered it no longer beneficial or consent was withdrawn. The primary end point was safety. Baseline data from the parent studies were used. Results: 52 pts were enrolled and received ENZA treatment (median age, 67 years [range, 54–88]). Median treatment duration was 443 days (range, 63–2010) since first administration and 392 days (range, 3–1926) in the extension study. In the extension, 43 pts (82.7%) experienced ≥1 any grade treatment-emergent adverse event (TEAE) with the most common (≥10% of pts) being fatigue (26.9% all grades, 13.5% grade 1, 7.7% grade 2, and 5.8% grade 3); arthralgia and back pain (13.5% each); and diarrhea, hot flush, and decreased appetite (11.5% each). Drug-related TEAEs (investigator assessed) were reported in 27 pts (51.9%) with the most common (≥5% of pts) being fatigue (17.3%); hot flush (11.5%); and diarrhea, hypophosphatemia, and muscle weakness (5.8% each). 17 pts (32.7%) had ≥1 serious TEAE. Eight drug-related serious TEAEs were reported in five pts (malignant neoplasm progression [3.8%]; acute pancreatitis, rectal haemorrhage, cerebrovascular accident, dysarthria, hemiparesis, and hypertensive crisis [1.9% each]). One (1.9%) death due to acute myocardial infarction (not drug-related) and four (7.7%) due to malignant neoplasm progression (two drug-related) were reported. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiogram were found. Conclusions: Long-term continued ENZA treatment is generally well tolerated, with a safety profile consistent with that previously reported. Clinical trial information: NCT01534052.

Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5015-5015
Author(s):  
David Margel ◽  
Avivit Peer ◽  
Yaara Ber ◽  
Sivan Sela ◽  
Liat Shavit Grievink ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Absolute Risk ◽  
Absolute Risk Reduction ◽  
Cerebrovascular Event ◽  
Gnrh Agonists ◽  
Open Label ◽  
Gnrh Antagonists

5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.

TNB585.001: A multicenter, phase 1, open-label, dose-escalation and expansion study of tnb-585, a bispecific T-cell engager targeting PSMA in subjects with metastatic castrate resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5092-TPS5092
Author(s):  
Ben Buelow ◽  
Pranjali Dalvi ◽  
Kevin Dang ◽  
Ashwin Patel ◽  
Kiran Johal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Specific Antigen ◽  
Outpatient Basis ◽  
Open Label ◽  
Psma Pet ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

TPS5092 Background: Prostate cancer (CaP) is the most common cancer in US men. Disseminated CaP invariably progresses to metastatic castrate-resistant prostate cancer (mCRPC). Current treatment options for mCRPC usually lead to therapeutic resistance, and novel therapies are urgently needed. PSMA is a prostate-specific antigen over-expressed on most mCRPC. Antibodies against PSMA have been used to create T-cell engaging bispecific Abs (TCEs) and chimeric antigen receptor T cells, but all such approaches to date induce frequent/severe cytokine release syndrome (CRS). We combined a high-affinity αPSMA moiety with a low-activating αCD3 binder to create TNB-585; in preclinical studies, TNB-585 showed equivalent anti-tumor efficacy but much reduced cytokine secretion compared to PSMA-targeted TCEs with a strongly activating αCD3 domain. TNB-585 also has a full length silenced Fc domain, conferring a 3-week half-life. A phase 1 study investigating the safety, pharmacokinetics (PK), anti-drug antibodies (ADA) and preliminary activity of TNB-585 in patients with mCRPC is ongoing and described. Methods: TNB585.001 (NCT04740034) is an open-label, multi-center study of TNB-585 in patients with mCRPC. The study is divided into escalation (Arm A, N=24) and expansion (Arm B, N=30) arms. Subjects who have received 2 or more prior lines of therapy are eligible. Prior exposure to PSMA-targeted therapy is permitted, as are well-controlled HBV, HCV, and HIV infection; subjects with secondary malignancies that do not interfere with the study may also be enrolled. Other key inclusion/exclusion criteria include EGFR of > 30ml/min and ECOG ≤ 2. TNB-585 is administered as an intravenous infusion every 3 weeks. Subjects must be admitted for 48 hours after their 1st dose; TNB-585 is given on an outpatient basis thereafter. Dose escalation is proceeding in Arm A via single patient cohorts until the onset of toxicity or activity; thereafter subjects enroll using a BOIN design. Arm B will start once the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) has been selected. Subjects will be treated until progression or unacceptable toxicity. In Arm A, occurrence of dose limiting toxicities (DLTs) will drive identification of the MTD (or RP2D) based on the BOIN escalation and de-escalation boundaries (λe of 0.236 and a λd of 0.358). In Arm B accrual will be suspended if more than 33% of subjects experience a DLT event. Adverse events (AEs), laboratory profiles, and vital signs will be assessed throughout the study. AEs are graded according to the NCI CTCAE, version 5.0. The activity endpoints (per PCWG3/RECIST1.1) include overall response rate, PSA50, PSA30, CTC counts, progression free survival and overall survival. The relationship between PSMA expression (via PSMA-PET) and activity will be assessed. Clinical trial information: NCT04740034.

Phase I/II safety and pharmacokinetic (PK) study of ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 43-43 ◽  
Author(s):  
Dana E. Rathkopf ◽  
Daniel Costin Danila ◽  
Michael J. Morris ◽  
Susan F. Slovin ◽  
Jill Elise Steinbrecher ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Pet Imaging ◽  
Nuclear Translocation ◽  
Tumor Regression ◽  
Partial Agonist ◽  
Phase 1 ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Open Label

43 Background: In CRPC, androgen receptor (AR) overexpression is associated with resistance to first-generation anti-androgen therapy such as bicalutamide. ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data shows that ARN-509 binds AR with 5-fold greater affinity than bicalutamide, and induces tumor regression in hormone-sensitive and CRPC xenograft models. Methods: In this open-label, Phase 1/2 study, mCRPC patients received ARN-509 orally on a continuous daily dosing schedule. In Phase 1 , 7 doses (30, 60, 90, 120, 180, 240, 300 mg) were tested using standard 3x3 dose escalation criteria to assess safety, PK, and determine the recommended Phase 2 dose (RP2D). Preliminary anti-tumor activity was assessed by PSA kinetics, radiographic responses, circulating tumor cells (CTCs), and FDHT-PET imaging. Results: Twenty-four patients (median age 68 yrs, Gleason Score 8; prior docetaxel 13%) were enrolled. The most common Grade 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related Grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden, which led to an additional 3 patients being enrolled at the highest dose with no further dose limiting toxicities. PK was shown to be linear and dose-dependent. Twelve patients (55%) had ≥ 50% PSA declines. To date, 7 patients have discontinued the study due to progression, with the longest patient still on study for more than 1 year. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Based on preclinical assessment of maximum efficacious dose, PK, and promising activity across all doses, 240 mg was selected as the RP2D. Conclusions: In this Phase 1 study, ARN-509 was shown to be safe and well tolerated, with promising preliminary activity based on PSA and pharmacodynamic evidence of AR antagonism. The Phase 2 portion of the study will enroll up to 90 patients with treatment-naïve non-metastatic and mCRPC.

A phase 1/1b multicenter, open-label, dose escalation and dose expansion study to evaluate the safety, pharmacokinetics, immunogenicity, and antitumor activity of MEDI3726 in patients with metastatic, castration-resistant prostate cancer who have received prior treatment with abiraterone or enzalutamide.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5088-TPS5088
Author(s):  
Mark T. Fleming ◽  
Richard Cathomas ◽  
Daniel Peter Petrylak ◽  
Judy Sing-Zan Wang ◽  
Neil Harrison Bander ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Dose Escalation ◽  
Phase 1 ◽  
Specific Antigen ◽  
Prior Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Label Dose

TPS5088 Background: Therapeutic advances have recently been achieved for patients with metastatic, castration-resistant prostate cancer (mCRPC) due to abiraterone acetate (ABI) and enzalutamide (ENZ). However, virtually all patients with mCRPC eventually progress in their disease, and further treatment options are limited. Prostate-specific membrane antigen (PSMA) is highly expressed in nearly all prostate cancers, and its expression is highest in mCRPC. MEDI3726 is an antibody-drug conjugate composed of anti-PSMA antibody derived from J591, site-specifically conjugated to the cytotoxic, DNA cross-linking, pyrrolobenzodiazepine dimer. MEDI3726 has demonstrated potent and specific in vitro and in vivo antitumor activity in human prostate cancer-derived preclinical models with different expression levels of PSMA. Methods: This is a first-in-human, phase 1/1b, multicenter, open-label, dose escalation and dose expansion study in patients who have received prior treatment with ABI or ENZ, with or without prior taxane-based chemotherapy in the mCRPC setting (NCT02991911). The primary objectives are to assess safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose or maximum administered dose of MEDI3726. The secondary objectives are to evaluate MEDI3726 for its antitumor activity (based on a composite response according to RECIST Version 1.1, a reduction in prostate-specific antigen level of 50% or more compared to baseline, or a conversion in the circulating tumor cell count [defined as a reduction from ≥5 cells/7.5 mL blood to < 5 cells/7.5 mL blood]), safety and tolerability in combination with ENZ, pharmacokinetics alone and in combination with ENZ, and immunogenicity. Recruitment is ongoing for this study, which has an estimated total target enrollment of 224 patients. Clinical trial information: NCT02991911.

A phase Ib/II open-label study of tazemetostat (TAZ) plus enzalutamide (E) or abiraterone/prednisone (A/P) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS255-TPS255
Author(s):  
Wassim Abida ◽  
Thomas Paul Bradley ◽  
Arash Rezazadeh ◽  
Lawrence Ivan Karsh ◽  
Ashley Ross ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Second Generation ◽  
Response Rate ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase 2 ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Phase 1B

TPS255 Background: The histone methyltransferase EZH2 is overexpressed in many cancers. In prostate cancer (PC), EZH2 inhibition may reverse acquired resistance to androgen inhibitors (AIs). Pts may initially respond to AIs, but pts who progress have limited treatment options. In phase 2 trials, TAZ, a selective, orally bioavailable, investigative small molecule EZH2 inhibitor, has demonstrated encouraging objective responses in B-cell lymphomas and molecularly defined solid tumors and a favorable safety profile. In PC preclinical models, TAZ + E or A/P showed a greater reduction in tumor growth than either drug alone. This study will evaluate the safety and efficacy of TAZ + E or A/P vs E or A/P alone in mCRPC. Methods: This phase 1b/2 study will enroll pts ≥18 years with progressive mCRPC, with or without prior second-generation AI treatment, and no prior chemotherapy. Phase 1b will identify the recommended phase 2 dose (RP2D) of TAZ when combined with E (160 mg/day) or A/P (A: 1000 mg/day; P: 5 mg twice-daily [BID]) and evaluate the safety and tolerability of each combination in treatment-naïve pts and pts previously treated with a second-generation AI. Using a modified 3+3 design (up to 48 pts: 18 for TAZ+A/P and 30 for TAZ+E), TAZ dosing will start at 400 mg BID, escalating to 800 mg BID in the TAZ+A/P group or 1600 mg BID in the TAZ + E group, if no dose-limiting toxicities are observed. Phase 2 will begin once the RP2D for each combination is determined. Efficacy and safety results from phase 1b will inform the final design for phase 2. Phase 2 will be an open label study where pts will be randomized to either E or A/P alone or in combination with TAZ. TAZ will be administered at the RP2D in continuous 28-day cycles for as long as pts tolerate treatment and continue AI therapy. Tumor assessments will be performed every 9 weeks for 6 months and every 12 weeks thereafter. Efficacy assessments include radiographic progression-free survival (primary endpoint), prostate-specific antigen (PSA) ≥50% response rate, time to PSA progression, time to subsequent systemic therapy, and objective response rate. Safety is a secondary endpoint.

A phase I/II study of combination olaparib and radium-223 in men with metastatic castration-resistant prostate cancer with bone metastases (COMRADE): A trial in progress.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS182-TPS182
Author(s):  
Justin Shaya ◽  
Wanling Xie ◽  
Biren Saraiya ◽  
Mamta Parikh ◽  
Edmund Folefac ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Bone Metastases ◽  
Phase 1 ◽  
Parp Inhibitors ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Radium 223

TPS182 Background: Radium-223 is an α-emitting radioisotope that induces DNA double-stranded breaks leading to cell death and has demonstrated improvement in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. PARP inhibitors, including olaparib and rucaparib, inhibit repair of DNA single-stranded beaks and have demonstrated clinical efficacy in mCRPC patients harboring alterations in the homologous recombination repair (HRR) pathway. In extensive preclinical cancer models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the clinical hypothesis that the combination of radium-223 with olaparib will demonstrate anti-tumor activity in patients with mCRPC irrespective of underlying HRR deficiency status. Methods: This is an open label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of olaparib in combination with radium-223 in men with mCRPC with bone metastases. Patient must have 2 or more bone metastases and at least 1 bone metastasis that has not been treated with prior radiation therapy. Key exclusion criteria include the presence of visceral metastases or malignant lymphadenopathy exceeding 4 cm and prior therapy with radium-223 and/or PARP inhibitors. The phase 1 component of the study uses a 3+3 dose escalation design to determine the recommended phase 2 dose of olaparib in combination with standard of care dosing of Radium-223. The primary endpoint of the phase 1 component is safety. The phase 2 component of the study is an open-label, randomized study evaluating the combination of olaparib and radium-223 compared to radium-223 alone. The primary endpoint of the phase 2 component is radiographic progression-free survival as defined by Prostate Cancer Working Group 3 guidelines for bone metastases and RECIST v1.1 for non-bone metastases. Secondary endpoints include time to PSA progression, PSA response, time to subsequent therapy, time to first skeletal event, overall survival, and safety. Exploratory endpoints include stratification of response based on HRR alterations, whole exome sequencing of plasma cell free DNA both at baseline, on treatment, and at progression, and evaluation of changes in the tumor immune microenvironment with therapy. As of October 1, 2020, the phase 1 component has completed accrual and we anticipate opening the phase 2 component by December 2020. Clinical trial information: NCT03317392.

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