Germline
In this multicentre case-control study, g
A total of 73 g
Median CSS (96%CI), yrs p-value g 11.3 (7-2-15.4) 6.3 (2.1-10.6) 0.041 g 13.4 (10-16.8) 6 (4.1-7.9) <0.001 NC NC + 17.6 (NR) 9.8 (5.9-13.8) <0.001 NC NC + 17.6 (NR) 4.8 (0-10.8) <0.001
PROREPAIR-A is the largest series of g
Spanish National Cancer Research Centre (CNIO).
CRIS Foundation, Prostate Cancer Foundation PCF Foundation.
R. Lozano Mejorada: Speaker Bureau/Expert testimony: Roche, Janssen-Cilag, Sanofi; Travel/Accommodation/Expenses: Roche, Janssen-Cilag, Astellas Pharma. E. Castro Marcos: Honoraria (self): Astellas Pharma, AstraZeneca, Bayer, Janssen-Cilag, Pfizer; Advisory/Consultancy: AstraZeneca, Bayer, Janssen; Research grant/Funding (institution): AstraZeneca, Bayer, Janssen; Travel/Accommodation/Expenses: Bayer, Janssen-Cilag, Roche, Astellas Pharma. F. Lopez Campos: Advisory/Consultancy: Astellas Pharma; Speaker Bureau/Expert testimony: Janssen, Astellas Pharma; Travel/Accommodation/Expenses: Astellas Pharma, Janssen; Research grant/Funding (self): Astellas Pharma. U. Anido: Honoraria (self): Pfizer, Novartis, Bayer, Bristol-Myers-Squbb, EUSA Pharma, Eisai, Astellas Pharma, Jassen-Oncology, Sanofi; Advisory/Consultancy: Bayer, Pfizer, Novartis, Ipsen, Eisai, EUSA Pharma, Sanofi; Research grant/Funding (self): Pierre Fabre; Travel/Accommodation/Expenses: Astellas Pharma, Novartis, Roche, Pfizer, Ipsen, Sanofi. M.J. Juan Fita: Advisory/Consultancy: Janssen; Speaker Bureau/Expert testimony: Sanofi, Astellas, Janssen, BMS, Bayer; Travel/Accommodation/Expenses: Janssen. N. Romero Laorden: Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Janssen, IPSEN, Astellas, Astra-Zeneca, MSD, Bayer, Tesaro, Sanofi. J. Rubio Briones: Advisory/Consultancy: Janssen, Astellas, Bayer; Research grant/Funding (self): HealthMDx. C.C. Pritchard: Advisory/Consultancy: AstraZeneca, Promega. D. Olmos Hidalgo: Honoraria (self): Bayer, Janssen, Sanofi; Advisory/Consultancy: AstraZeneca, Bayer, Clovis Oncology, Daiichi-Sankyo, Janssen, MSD, Roche ; Research grant/Funding (institution): Astellas, AstraZeneca, Bayer, Genentech, Janssen, Medication, MSD, Pfizer, Roche, Tokai Pahrmaceutics; Travel/Accommodation/Expenses: Bayer, Ipsen, Janssen, Roche. All other authors have declared no conflicts of interest.
Up to 30% of mCRPC men harbor DDR defects and may benefit from PARP inhibitors (PARPi) after abiraterone/enzalutamide and docetaxel failure. CBZ was recently shown to improve overall survival (OS) in this population, though benefit by DDR status is unknown. We assessed CBZ activity in men with mCRPC according to their DDR status.
In this retrospective multicenter study, mCRPC patients (pts) who received CBZ were included if their DDR profile from tissue was available. Gene panels included at least
A total of 190 pts were included: 95 DDR+ and 95 DDR-. DDR+ pts were younger than DDR- (66 vs 69 years, p=0.026). The Gleason score was ≥8 in 66% and 55%, metastases (mts) were found at diagnosis in 51% and 41%, respectively. At CBZ start, pts had received a median of 2 prior life-prolonging agents, visceral mts in 24% and 26%, ECOG ≤1 in 78% and 80%, and a median PSA of 91 and 77 ng/ml, respectively. Among DDR+ pts, 40 (42%) had BRCA defects and 43 (45%) received a PARPi. A 50% PSA decline was achieved with CBZ in 29 (32%) and 33 (36%) in DDR+ and DDR- pts (p=0.64). Median rPFS was 5.33 months [95%CI 4.34-7.04] and 5.75 months [95%CI 4.67-7.27] (p=0.55), and median OS was 15.4 months [95%CI 12.16-26.6] and 11.5 months [95%CI 9.76-14.4] (p=0.036), respectively. An ECOG≥2 and visceral mts were independently associated with shorter OS. Outcomes of DDR+ pts are depicted in the Table, according to their sequence with PARPi.
CBZ no PARPi n=53 CBZ before PARPi n=24 CBZ after PARPi n=18 Median prior lines 2 2 3 ECOG ≤1 36/53 (72%) 22/24 (92%) 12/18 (67%) Visceral mts 13/53 (25%) 5/24 (21%) 4/18 (22%) 50% PSA decline All pts BRCA+ 16/51 (31%) 10/39 (26%) 10/24 (42%) 6/14 (43%) 3/18 (17%) 0/10 (0%) Median rPFS (months) [95%CI] 6.15 [3.68-8.38] 5.97 [3.98-8.05] 3.09 [0.98-6.57] Median OS (months) [95%CI] 12.9 [10.2-20] 42.5 [20.2-67.4] 7.2 [5.29-13.41]
CBZ is active in both DDR+ and DDR- mCRPC men. Activity may be lower in pts pre-treated with a PARPi, pending validation.
Karim Fizazi.
Has not received any funding.
C. Llacer Perez: Travel/Accommodation/Expenses: Astellas Pharma, Angelini Pharma. G. Gravis Mescam: Honoraria (institution): Pfizer, BMS, MSD, AstraZeneca, Astellas, Janssen, Bayer; Advisory/Consultancy: BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, Bayer; Travel/Accommodation/Expenses: BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, MSD. A. Fléchon: Honoraria (self): AZ Sanofi, Astellas, Janssen AAA; Travel/Accommodation/Expenses: AZ Sanofi, Astellas, Janssen. P. Barthélémy: Honoraria (self): Astellas; Advisory/Consultancy: Janssen-Cilag, Sanofi, MSD, BMS, Pfizer, Novartis, Ipsen, Roche; Travel/Accommodation/Expenses: BMS, Amgen, Pfizer, Janssen-Cilag, Roche, Ipsen. C. Helissey: Advisory/Consultancy: Sanofi, Janssen, Astellas, Roche, AstraZeneca. C. Pobel: Travel/Accommodation/Expenses: Sanofi, Ipsen, Sandoz. E. Castro Marcos: Advisory/Consultancy: AstraZeneca, Bayer, Janssen; Speaker Bureau/Expert testimony: Astellas, AstraZeneca, Bayer, Janssen, Pfizer; Research grant/Funding (institution): AstraZeneca, Bayer, Janssen; Travel/Accommodation/Expenses: AstraZeneca, Bayer, Janssen, Roche. A. Thiery-Vuillemin: Honoraria (self): Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche/Genentech, Bristol-Myers Squibb, MSD, Astellas Pharma; Advisory/Consultancy: Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche, Bristol-Myers Squibb, MSD, Astellas Pharma; Research grant/Funding (institution): Pfizer; Travel/Accommodation/Expenses: Roche, MSD, Janssen, Bristol-Myers Squibb. G. Baciarello: Honoraria (self): Janssen, Roche; Advisory/Consultancy: Amgen, Astellas Oncology, Janssen, Roche; Travel/Accommodation/Expenses: Astellas Oncology, Ipsen, Janssen, Roche. E. Orillard: Honoraria (self): Astellas, Janssen; Travel/Accommodation/Expenses: Pfizer, Amgen. K. Fizazi: Honoraria (self): Astellas Pharma, Bayer, Janssen, Sanofi; Advisory/Consultancy: Amgen (Inst), Astellas Pharma, AstraZeneca (Inst), Bayer, Curevac (Inst), ESSA (Inst), Janssen Oncology, Orion Pharma GmbH, Sanofi; Travel/Accommodation/Expenses: Amgen, Janssen. All other authors have declared no conflicts of interest.
Male-carriers of
We recruited men aged 40–70 with
We recruited 188 men (108 BRCA1, 80 BRCA2), mean age 54Y (±9.8). One hundred and ten (57%) had either elevated age-stratified PSA (75; 40%), a suspicious MRI lesion (67; 36%), or both (32; 17%). Of these, 92 (85%) agreed to agreed to a biopsy. Sixteen (8.5%) were diagnosed with PCa; 44% of tumors were classified as intermediate or high risk. mpMRI based screening missed only one of the cancers (6%), while age stratified PSA would have missed five (31%). Decision curve analysis showed that mpMRI screening regardless of PSA had the highest net benefit for PCa diagnosis, especially among men younger than 55Y. We found no difference in the risk of PCa between BRCA1 and BRCA2 (8.3% vs. 8.7%, p=0.91).
Screening Strategy Biopsies avoided n, (%) Cancer detected n, (%) Cancer missed n, (%) Negative predictive value Positive predictive PSA>3 67 (73%) 5 (31%) 11 (69%) 83.6% (78.1-87.9) 20% (9.9-36.2) Elevated Age-stratified PSA 32 (35%) 5 (31%) 11 (69%) 84.4% (71.1-92.2) 18.3% (13.4-24.5) PI-RADS≥3 29 (32%) 15 (94%) 1 (6%) 96.6% (80.4-99.5) 23.8% (20.2-27.9) PSA>3 AND PI-RADS≥3 74 (80%) 9 (56%) 7 (44%) 90.6% (84.5-94.4) 50% (32.1-67.9) Elevated Age-stratified PSA AND PI-RADS≥3 61 (66%) 10 (63%) 6 (27%) 90% (82.5-94.5) 31.3% (21.3-43.3)
PCa is prevalent among
NCT02053805.
David Margel.
American Society of Clinical Oncology (ASCO).
D. Margel: Research grant/Funding (self), Career Development Award 2015: ASCO. All other authors have declared no conflicts of interest.
VERU-111 is an oral, a & b tubulin inhibitor of microtubule polymerization with no affinity for multidrug resistance proteins. A phase 1b/2 clinical study is being conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with progressive mCRPC resistant to androgen blocking agents +/- a taxane.
Phase 1b study was a 3x3 design with escalating oral dosing of 4.5 mg to 81 mg (7 days on drug/14 days off per 21 day cycle). After no dose limiting toxicity was observed, the dose was increased in the next cohort. The schedule was also expanded in those completing the 7 days on/14 days off cycle to continuous dosing/cycle.
30 taxane-naïve mCRPC men with a median age of 76 (61-92) were enrolled. 8 received prior enzalutamide, 12 abiraterone and 10 both. 8 men had bone mets, 5 lymph node, 5 mixed and 1 had soft tissue metastases. The MTD of VERU-111 is 72mg (3 /11 men had Grade 3 diarrhea). No Grade 3 diarrhea was observed at doses <72 mg per day. At doses < 72mg/d, the most common AEs were mild to moderate nausea, vomiting, diarrhea, and fatigue, with no observed neurotoxicity or neutropenia. Antitumor activity was assessed by PSA and bone/CT scans in men that were treated for ≥ 4 continuous 21-day cycles. 5/8 (63%) had PSA declines: 4 (50%) men had ≥ 30% and 2(25%) ≥ 50% declines compared to their 21 day cycle baseline. Based on PCWG3/RECIST 1.1 criteria, objective tumor responses were seen in 2 men (soft tissue and bone) and 5/8 (63%) had stable disease. Objective responses and PSA declines lasted > 12 weeks. Median duration of response has not been reached as 7/8 of the men are still being treated on study with a current duration of 10 months (6-15 months) and three additional men have not yet completed ≥ 4 continuous 21-day cycles.
The phase 1b portion demonstrates that oral VERU-111 has a favorable safety profile allowing for chronic administration and significant/durable antitumor activity. The daily dose of 63mg is being tested in the phase 2 portion. Oral administration, safe long-term treatment and evidence of antitumor activity highlight a potential prominent role of VERU 111 for the treatment of men with mCRPC who failed an androgen blocking agent.
NCT03752099.
Veru Inc.
Veru Inc.
M. Markowski: Research grant/Funding (institution): Veru Inc. M.A. Eisenberger: Shareholder/Stockholder/Stock options, Officer/Board of Directors: Veru Inc. R. Tutrone: Research grant/Funding (institution): Veru Inc. C. Pieczonka: Research grant/Funding (institution): Veru Inc. R.H. Getzenberg: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Veru Inc. D. Rodriguez: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Veru Inc. K.G. Barnette: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Veru Inc. M.S. Steiner: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Veru Inc. D.R. Saltzstein: Research grant/Funding (institution): Veru Inc. All other authors have declared no conflicts of interest.
Immune checkpoint inhibitors have minimal activity in unselected CRPC patients (pts). Combination regimens that generate a tumor-directed immune response (vaccine) and facilitate the resulting anti-tumor immune activity (checkpoint blockade, cytokines) have shown synergy in preclinical models. BNVax is a therapeutic poxviral vaccine targeting brachyury, a transcription factor involved in invasion and metastasis. BA is a bifunctional fusion protein: anti-PD-L1 monoclonal antibody fused to the TGF-β-RII receptor extracellular domain (a TGF-β trap). N-803 is an IL-15 superagonist complex. Here we report an interim efficacy analysis of the QuEST1 study, aimed to rapidly interrogate safety and efficacy of immunotherapy combinations in CRPC.
Asymptomatic/minimally symptomatic CRPC pts received BNVax + BA (Arm 2.1) or BNVax + BA + N-803 (Arm 2.2). BNVax is given as 2 prime doses followed by boosts. BA 1,200 mg intravenously and N-803 15 μg/kg subcutaneously are given every 2 weeks. Efficacy is defined as objective response by RECIST v1.1 or PSA decrease ≥ 30% sustained for ≥ 21 days. Safety was a secondary endpoint.
As of 4/26/20, 22 CRPC pts enrolled and had 3 to 17 months follow up. 1/13 pts (Arm 2.1) had a PSA response sustained for 13 months. 4/9 (44%) pts (Arm 2.2) had sustained PSA responses; 2 of these pts had confirmed PR, including 1 pt who progressed on abiraterone and enzalutamide. There were no DLTs or grade >3 treatment-related adverse events (TRAEs). Grade 3 TRAEs: 1 pancreatitis (Arm 2.1), 1 secondary adrenal insufficiency (Arm 2.1), and 1 hyperglycemia due to new onset diabetes mellitus (Arm 2.2).
PSA Response/ # Evaluable (%) # with Measurable Disease by RECIST BOR in Pts with Measurable Disease by RECIST CR PR SD PD BNVax + BA 1/13 (7.8%) 3 0 0 1 2 BNVax + BA + N-803 4/9 (44%) 3 0 2 1 0
BVax + BA + N-803 demonstrated a manageable safety profile and preliminary evidence of efficacy in CRPC. Addition of N-803 in Arm 2.2 was associated with more activity in this small sample. Arm 2.2 met the predetermined threshold for efficacy and will expand (n=25).
NCT03493945. First posted April 11, 2018.
Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Center for Cancer Research, National Cancer Institute.
The National Cancer Institute, National Institutes of Health has Cooperative Research and Development Agreements (CRADAs) with Bavarian Nordic, Merck KGaA, and ImmunityBio.
All authors have declared no conflicts of interest.
There is growing evidence of antineoplastic properties of metformin (MET) in prostate cancer (PCa). Many observational studies suggested that using MET was associated with improvement in overall survival in PCa patients. MET was reported to be associated with reduction of risk of development of castration-resistant state (CRPC). In addition, when MET was combined to ADT or biclutamide, it augmented the antiproliferative effect of these drugs.
a total of 124 men were randomly allocated into two arms (62 in MET arm, 62 in SOC arm). The baseline demographic and disease characteristics were comparable between two arms. Over a median follow up of 18 months, there were 12 deaths in the MET arm versus 17 deaths in the control arm (P= 0.2). Median time to CRPC was longer in MET arm 29 months (95%CI 25-33) compared to control arm 20 months (95% CI 16-24) (P=0.01). After subgroup analysis, the median time to progression to CRPC was longer at MET arm in high risk localized prostate cancer (P=0.02), in mHSPC patients with low tumor volume was of borderline significance (P= 0.06), and in those with node positive (N1) disease was highly significant (P=0.001). While in patients with high tumor volume, there was no significant difference regarding the median time to CRPC among the two groups (P=0.9). Regarding secondary objective, there was no significant difference between two arms in overall survival (OS) (P= 0.1) or PSA response rate (P=0.5). Notably no significant adverse events were reported in MET arm apart of self-limiting diarrhea.
Metformin potentially lengthen time to CRPC in advanced PCa patients when combined with ADT especially in those with high risk localized PCa, clinically node positive and in those with low tumor volume metastatic hormone naive patients.
NCT03137186.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Oligo-metastatic prostate cancer is recognized as an intermediate stage between localized disease and widespread metastases. The role of radical local therapy (RLT) to the primary tumor for these patients is unclear. We conducted this phase 2 randomized trial to investigate if radical prostatectomy (RP) or prostate radiotherapy (RT) benefits these patients (NCT02742675).
Oligo-metastases was defined as ≤ 5 bone or extra-pelvic lymph node metastases and no visceral metastases. Patients were randomly assigned (1:1) to receive androgen deprivation therapy (ADT) or ADT plus RLT. For patients allocated to ADT+RLT group, RP was recommended with priority, while RT was administrated to those refused RP and those with unresectable primary tumor after 1-3 months induced ADT. The primary outcome was radiographic progression-free survival (rPFS) and the secondary outcome was overall survival (OS).
A total of 200 patients were enrolled between Sept 1, 2015 and Mar 10, 2019. The median age was 68 years and the median PSA at diagnosis was 98.8 ng/ml. Bone metastases and distant lymph node metastases exited in 96% and 15% of all patients. 96 of 100 patients in ADT+RLT group received RLT including 85 RP and 11 RT. After a median follow-up of 28 months, radiographic progression was observed in 19 of 100 patients in ADT+RLT group and 33 of 100 patients in ADT group. The median rPFS was not reached in ADT+RLT group and 50 months in ADT group (HR = 0.50; 95% CI, 0.28 to 0.87; p = 0.015). RLT related complications occurred in 24 of 85 RP patients (including 3 grade 3-4 complications) and 5 of 11 RT patients. In order to evaluate the OS, longer follow-up period is required.
Local therapy to the primary tumor improves rPFS in patients with newly diagnosed, oligo-metastatic prostate cancer.
NCT02742675.
Bo Dai.
Fudan University Shanghai Cancer Center.
All authors have declared no conflicts of interest.