Effective therapies for pts with treatment-refractory mCRPC are an important unmet medical need. Niraparib is a highly selective poly ADP-ribose polymerase (PARP) inhibitor of PARP-1 and PARP-2 DNA-repair polymerases.
GALAHAD is an ongoing open-label phase II study assessing niraparib (300 mg daily) in pts with mCRPC and DRD with disease progression on taxane and androgen receptor-targeted therapy. DRD status was evaluated by a plasma or tissue-based test and defined as having biallelic alterations in BRCA1/2 (BRCA), ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2. Primary endpoint was objective response rate (ORR) by RECIST 1.1 with no evidence of bone progression as per the PCWG3 criteria. Composite response rate (CRR) was defined as ORR, conversion of circulating tumor cells to < 5/7.5 mL blood, or ≥ 50% decline in prostate specific antigen.
As of 23 May 2019, 165 pts were enrolled, of whom 81 had biallelic DRD (46 BRCA and 35 non-BRCA) and had a minimum of 16 weeks of follow up. 51/81 had measurable disease at baseline (29 BRCA and 22 non-BRCA); 47% of pts had visceral metastases. Median follow-up in BRCA and non-BRCA was 7.3 and 6.4 mo, respectively. In BRCA, ORR was 41% and CRR was 63% (table); median duration of objective response was 5.5 mo (range: 3.5–9.2). 7/12 BRCA responses were ongoing. Median rPFS and OS in BRCA were 8.2 and 12.6 mo, respectively. In non-BRCA, objective response was noted in 2/22 pts (both had FANCA) and CRR was 17%; durations of objective response were 3.8 and 6.5 mo, respectively. Grade 3/4 treatment-emergent adverse events were mostly hematologic—anemia (29%), thrombocytopenia (15%) and neutropenia (7%)—and managed with dose interruption or modification. LBA50 CI, confidence interval; CRR, composite response rate; CTC, circulating tumor cells; DRD, DNA-repair gene defects; ORR, objective response rate; OS, overall survival; PSA50, ≥50% decline in prostate-specific antigen; rPFS, radiographic progression-free survival.All biallelic DRD (n = 81) Response BRCA1/2 Non-BRCA n (%) (95% CI) (n = 46) (n = 35) Objective RR 12/29 (41) (23.5, 61.1) 2/22 (9) (1.1, 29.2) PSA50 23/46 (50) (34.9, 65.1) 1/35 (3) (0.1, 14.9) CTC Conversion 18/38 (47) (31.0, 64.2) 5/24 (21) (7.1, 42.2) CRR 29/46 (63) (47.6, 76.8) 6/35 (17) (6.6, 33.7) Median rPFS, mo (95% CI) 8.2 (5.2, 11.1) 5.3 (1.9, 5.7) Median OS, mo (95% CI) 12.6 (9.2, 15.7) 14.0 (5.3, 20.1)
Niraparib demonstrates clinical activity in pts with treatment-refractory mCRPC with durable responses particularly in biallelic BRCA mutation carriers.
NCT02854436.
Writing assistance was provided by Ramji Narayanan of SIRO Clinpharm Pvt Ltd and funded by Janssen Global Services, LLC.
Janssen Research & Development, LLC.
Janssen Research & Development, LLC.
S.K. Sandhu: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: Merck. W.K. Kelly: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Novartis. H.I. Scher: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Asterias Biotherapeutics; Advisory / Consultancy: Ambry Genetics Corporation; Advisory / Consultancy: Konica Minolta,Inc; Advisory / Consultancy: Janssen Biotech, Inc; Advisory / Consultancy, Research grant / Funding (institution): Janssen Research & Development; Advisory / Consultancy, Travel / Accommodation / Expenses: OncLive Insights; Advisory / Consultancy: Physician Education Resource; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: WIRB-Copernicus Group; Research grant / Funding (institution): Illumina ; Research grant / Funding (institution): Innocrin Pharma; Travel / Accommodation / Expenses: Physician Education Resource. E. Efstathiou: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen-Cilag; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Innocrin Pharma; Advisory / Consultancy: MSD; Advisory / Consultancy: Tolmar. P.N. Lara: Honoraria (self), Advisory / Consultancy: Pfizer; Advisory / Consultancy: AbbVie; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: CellMax Life; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Nektar; Advisory / Consultancy: Turnstone Bio; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Genentech ; Research grant / Funding (institution): GlaxoSmithKline ; Research grant / Funding (institution): Heat Biologics; Research grant / Funding (institution): Incyte ; Research grant / Funding (institution): Janssen Biotech; Research grant / Funding (institution): Millennium, Pharmacyclics, Polaris,TRACON Pharma . E.Y. Yu: Advisory / Consultancy: Amgen; AstraZeneca; Bayer; Churchill Pharmaceuticals; EMD Serono; Incyte; Janssen; Merck; QED; Tolmar; Research grant / Funding (institution): Agensys; Astellas Pharma; Bayer; Dendreon; Genentech/Roche; Merck; Seattle Genetics. D.J. George: Honoraria (self): Bayer; Exelixis; Sanofi; Advisory / Consultancy: Astellas Pharma; Bayer; Bristol-Myers Squibb; Exelixis; Genentech; Innocrin Pharma; Janssen; Merck Sharp & Dohme; Myovant Sciences; Pfizer; Sanofi; Speaker Bureau / Expert testimony: Bayer; Exelixis; Sanofi; Research grant / Funding (institution): Acerta Pharma ; Astellas Pharma ; Bayer ; Bristol-Myers Squibb ; Dendreon ; Exelixis ; Innocrin Pharma ; Janssen Oncology ; Novartis ; Pfizer ; Travel / Accommodation / Expenses: Bayer; Exelixis; Merck; Pfizer; Sanofi. K.N. Chi: Honoraria (self): Astellas Pharma; Bayer; Janssen; Sanofi; Advisory / Consultancy: Amgen; Astellas Pharma; Bayer; ESSA; Janssen; Lilly/ImClone; Sanofi; Research grant / Funding (institution): Astellas Pharma ; Bayer ; Bristol-Myers Squibb ; Janssen ; Lilly/ImClone ; Merck ; Roche ; Sanofi ; Tokai Pharmaceuticals . F. Saad: Honoraria (self): Astellas Pharma; AstraZeneca; Bayer; Janssen Oncology; Sanofi; Advisory / Consultancy: Astellas Pharma; AstraZeneca/MedImmune; Bayer; Janssen Oncology; Sanofi; Research grant / Funding (institution): Astellas Pharma ; AstraZeneca ; Bayer ; Janssen Oncology ; Sanofi . J. Summa: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. J.M. Freedman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. G.E. Mason: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. E. Zhu: Full / Part-time employment: Janssen. D. Ricci: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. J.S. Simon: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. S. Cheng: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. All other authors have declared no conflicts of interest.
Although once considered a homologous recombination DNA repair gene, CDK12 is now thought to have a distinct role in maintaining genomic stability. In prostate cancer, inactivating CDK12 mutations lead to gene fusion-induced neoantigens and possibly sensitivity to PD1 inhibitors.
We conducted a retrospective multicenter study to identify advanced prostate cancer patients with loss-of-function CDK12 mutations. We characterized their clinical features and therapeutic outcomes, including sensitivity to PARP and PD1 inhibitors.
58 men with at least monoallelic CDK12 alterations were identified from 9 academic centers; 28 (48%) had biallelic inactivation. Tissue for genomics was from primary tumors in 45 cases (77%) and from metastatic sites in 13 cases (23%). All CDK12 mutations were somatic-only. Median age at diagnosis was 60 y (41–78 y), 71%/29% were white/nonwhite, 79% had Gleason sum 9-10, 10% had ductal/intraductal histology, 76% had stage T3/T4 disease, 47% had metastases at diagnosis, and the median PSA was 24 ng/mL. Of those undergoing primary ADT (± Abi, ± Doce) for advanced disease (n = 54), only 85% had a PSA50 response, with median PFS of 11.8 (95% CI 8.3–15.4) mo; OS from ADT initiation was 40.8 (95% CI 18.7–53) mo. Of those receiving first-line Abi/Enza for mCRPC (n = 34), only 47% had a PSA50 response, with median PFS of 4.3 (95% CI 2.6–6.0) mo. Of those receiving a first Taxane agent for mCRPC (n = 20), only 35% had a PSA50 response, with median PFS of 4.0 (95% CI 2.6–5.3) mo. Eleven men received a PARP inhibitor (10 Olaparib, 1 Rucaparib): none had a PSA50 response, and median PFS was 3.6 (95% CI 3.0–4.2) mo. Eight men received a PD1 inhibitor as 4th to 6th-line mCRPC therapy (5 Pembro, 3 Nivo): 38% had a PSA50 response, and median PFS was 6.6 (95% CI 2.3–10.8) mo.
CDK12-altered prostate cancer is an aggressive subtype presenting at young age, with high Gleason grade, and often with de novo M1 disease at diagnosis. Outcomes to hormonal and taxane therapies are poor, and PARP inhibitors are also ineffective. A proportion of these patients respond favorably to PD1 inhibitors, implicating CDK12 deficiency in immunotherapy responsiveness.
Emmanuel S. Antonarakis.
Has not received any funding.
E.S. Antonarakis: Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy: ESSA; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Johnson & Johnson; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly; Licensing / Royalties: Qiagen. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Celldex. B.L. Maughan: Advisory / Consultancy: Peloton Therapeutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Tempus; Advisory / Consultancy: Bayer; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Astellas. M. Hussain: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): Genentech; Honoraria (self): Sanofi Genzyme; Honoraria (self): Research To Practice; Honoraria (self): Aptitude Health; Honoraria (self): Epics. All other authors have declared no conflicts of interest.
Rucaparib has shown antitumour activity in pts with mCRPC and a deleterious DDR gene alteration. We present here updated analyses.
TRITON2 (NCT02952534) is an ongoing phase 2 study evaluating rucaparib 600 mg BID in pts with mCRPC and a deleterious germline or somatic alteration in BRCA1, BRCA2, ATM, CDK12, or other prespecified DDR gene. Eligible pts have progressed on 1–2 lines of androgen receptor–directed therapy and 1 line of taxane-based chemotherapy for mCRPC.
As of 15 Feb 2019 (visit cutoff), 136 pts had received rucaparib and had ≥16 weeks of follow-up: 62 with a BRCA2 and 7 with a BRCA1 alteration (BRCA pts), 41 with an ATM alteration (ATM pts), 14 with a CDK12 alteration (CDK12 pts), and 12 with another DDR gene alteration (other DDR pts). Median duration of follow-up was 11.4 mo (range 4.0–24.0). PSA and objective response rates (ORR) were 53.6% and 47.5% in BRCA pts (Table). ORR in BRCA pts with somatic alterations was 56.5% (95% CI, 34.5–76.8; 13/23) and 40.0% (95% CI, 16.3–67.7; 6/15) in pts with germline alterations. Some ATM and CDK12 pts had a reduction in target lesion diameter (≥30% decrease in 3 ATM pts) or PSA level (≥50% decrease in 3 ATM pts and 2 CDK12 pts); however, no objective responses were observed in ATM or CDK12 pts, and only 1 ATM pt and 1 CDK12 pt had a confirmed PSA response. Median (95% CI) time to PSA progression was 6.5 (5.7–7.5) mo, 3.1 (2.8–4.6) mo, and 3.5 (2.8–4.6) mo in BRCA, ATM, and CDK12 pts. The most common grade ≥3 treatment-emergent adverse event was anaemia/decreased haemoglobin (16.2%). 846PD Includes 2 pts each with an alteration in FANCA, NBN, or PALB2 and 1 each with an alteration in BRIP1, BRIP1/CHEK2, CDK12/CHEK2, CHEK2, RAD51, or RAD51B. Defined as confirmed complete or partial response per modified RECIST/PCWG3. Includes pts who had measurable disease at baseline per the investigator and ≥16 weeks of follow-up. Responders include 1 pt each with a BRIP1, FANCA, PALB2, or RAD51B alteration. Defined as ≥ 50% reduction in PSA from baseline. Includes pts who had ≥16 weeks of follow-up. Responders include 2 pts with a PALB2 alteration and 1 pt each with a BRIP1, FANCA, or RAD51B alteration. CI, confidence interval; PSA, prostate-specific antigen.By DDR gene with alteration BRCA ATM CDK12 Other DDR genea Baseline disease characteristics, n/N (%) Gleason score ≥8 48/69 (69.6) 17/41 (41.5) 13/14 (92.9) 8/12 (66.7) Measurable disease at baseline (per investigator) 40/69 (58.0) 15/41 (36.6) 9/14 (64.3) 12/12 (100) Efficacy outcomes, n/N (%) [95% CI] Confirmed investigator-assessed objective responseb 19/40 (47.5) 0/15 (0) 0/9 (0) 4/12 (33.3)c [31.5–63.9] [0–21.8] [0–33.6] [9.9–65.1] Complete response 2/40 (5.0) 0 0 1/12 (8.3) Partial response 17/40 (42.5) 0 0 3/12 (25.0) Confirmed PSA responsed 37/69 (53.6) 1/41 (2.4) 1/14 (7.1) 5/12 (41.7)e [41.2–65.7] [0.1–12.9] [0.2–33.9] [15.2–72.3]
Consistent with prior reports, rucaparib demonstrates promising efficacy in pts with mCRPC and a germline or somatic BRCA or other DDR gene alteration. No objective responses have been observed in pts with an ATM or CDK12 alteration. The safety profile of rucaparib is consistent with prior reports in ovarian and prostate cancer. Updated data will be presented.
NCT02952534.
Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA), funded by Clovis Oncology, Inc. (Boulder, CO, USA).
Clovis Oncology, Inc.
Clovis Oncology, Inc.
W. Abida: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis Oncology, Inc.; Advisory / Consultancy: Janssen; Advisory / Consultancy: MORE Health; Advisory / Consultancy: ORIC Pharmaceuticals; Research grant / Funding (institution), Travel / Accommodation / Expenses: GlaxoSmithKline; Honoraria (self): Caret Healthcare; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Zenith Epigenetics. A. Patnaik: Advisory / Consultancy: Janssen; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GlaxoSmithKline. J. Shapiro: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Astellas Pharma, Inc.; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche. N.J. Vogelzang: Advisory / Consultancy: Astellas Pharma, Inc.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Caris; Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi Aventis. J. Zhang: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (institution): Astellas Pharma, Inc.; Research grant / Funding (institution): Bayer. A.D. Simmons: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. D. Despain: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. M. Dowson: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. T. Golsorkhi: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. S. Chowdhury: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Clovis Oncology, Inc.; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas Pharma, Inc.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi. All other authors have declared no conflicts of interest.
A proportion of patients (pts) with mCRPC have tumour cells harbouring HRRm that may confer sensitivity to PARP inhibition. The PROfound study (NCT02987543) is a phase III, randomized, multicentre trial evaluating the efficacy and safety of the PARP inhibitor olaparib versus physician’s choice of enzalutamide or abiraterone acetate in pre-treated mCRPC pts with a qualifying HRRm. Here we report the prevalence of HRRm and co-occurring HRRm in pts screened for PROfound.
An investigational next-generation sequencing assay developed in partnership with Foundation Medicine Inc. (FMI) was used to prospectively select patients harbouring HRRm in their tumour tissue. This tumour tissue test reports deleterious or suspected deleterious alterations (‘qualifying mutations’) in 15 HRR genes. Tissue samples were clinically heterogenous regarding location and timing. Pts that had a qualifying mutation and who met the remaining eligibility requirements were randomized to the trial. The study comprised two cohorts; Cohort A: pts with mutations in BRCA1, BRCA2 or ATM (assigned regardless of any co-occurring mutation in other genes); Cohort B: 12 other HRR genes.
Of 4426 screened pts, 4047 had samples tested at FMI, of whom 2793 (69%) yielded an interpretable result. A qualifying HRRm was detected in 778 (27.9%) pts and the prevalence of HRRm in genes included in Cohort A was 17.1%. A co-occurring qualifying HRRm alteration in ≥ 1 gene was detected in 59 (7.6%) patients, most commonly BRCA2 (n = 30), CDK12 (n = 24) or ATM (n = 13; Table). 847PD Pts with a mutation in more than one gene are re-counted for each co-occurring mutationGene No. of patients Prevalence in pts successfully tested, % (n = 2793) Prevalence in all HRRm-detected patients, % (n = 778) Co-occurring qualifying HRRm (no. of patients) BRCA2 272 9.7 35.0 ATM (5); BARD1 (3); CDK12 (9); CHEK2 (7); PPP2R2A (6); RAD51B (1); RAD51C (1); RAD51D (1) ATM 177 6.3 22.8 BARD1 (1); BRCA1 (1); BRCA2 (5); CDK12 (2); CHEK2 (1); FANCL (1); PALB2 (1); PPP2R2A (1); RAD51B (2) BRCA1 35 1.3 4.5 ATM (1); BARD1 (1); CDK12 (3); PPP2R2A (1); RAD54L (2) CDK12 199 7.1 25.6 ATM (2); BARD1 (3); BRCA1 (3); BRCA2 (9); BRIP1 (1); CHEK1 (2); CHEK2 (3); PALB2 (2); PPP2R2A (2); RAD51B (1) CHEK2 44 1.6 5.7 ATM (1); BRCA2 (7); CDK12 (3); RAD51D (1) PPP2R2A 41 1.5 5.3 ATM (1); BRCA1 (1); BRCA2 (6); CDK12 (2); PALB2 (1); RAD54L (1) PALB2 15 0.5 1.9 ATM (1); BRIP1 (1); CDK12 (2); PPP2R2A (1); RAD51D (1) BRIP1 14 0.5 1.8 CDK12 (1); PALB2 (1) RAD54L 11 0.4 1.4 BRCA1 (2); PPP2R2A (1) BARD1 11 0.4 1.4 BRCA1 (1); BRCA2 (3); CDK12 (3) RAD51B 10 0.4 1.3 ATM (2); BRCA2 (1); CDK12 (1) RAD51D 6 0.2 0.8 BRCA2 (1); CHEK2 (1); PALB2 (1) CHEK1 4 0.1 0.5 CDK12 (2) FANCL 2 0.1 0.3 ATM (1) RAD51C 1 0.04 0.1 BRCA2 (1)
This is the largest study to date with central prospective HRRm tissue testing in prostate cancer. HRRm were most common in BRCA2, followed by ATM and CDK12. Further analyses are warranted to help understand if there is any correlation between clinical/demographic characteristics and HRRm.
NCT02987543.
Sarah Bulman, Mudskipper Business Ltd; funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).
AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
J.S. de Bono: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: GSK; Licensing / Royalties, Abiraterone rewards to Inventors with royalties paid to institution, no personal income: Janssen Oncology; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Genmab, Orion Pharma, Qiagen, Taiho Pharma, Vertex; Licensing / Royalties, A patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income: N/A. K. Fizazi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AAA; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Curevac; Honoraria (self), Advisory / Consultancy: Essa; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Orion; Honoraria (self), Advisory / Consultancy: Sanofi. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen. N. Shore: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer. S.K. Sandhu: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche Genentech; Research grant / Funding (institution): Endocyte. N. Mehra: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Sanofi. M. Kolinsky: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Novartis. M. Özgüroǧlu: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Janssen; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Roche; Travel / Accommodation / Expenses: BMS. N. Matsubara: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Speaker Bureau / Expert testimony: Chugai; Research grant / Funding (institution): Eisai. C. Gedye: Non-remunerated activity/ies: AbbVie, Astellas, Amgen, Bristol-Myers Squibb, AstraZeneca, Merck, Sharp & Dohme, Pfizer, Losen; Travel / Accommodation / Expenses: Astellas, Bristol-Myers Squibb, Merck, Sharp & Dohme. C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Corcoran: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C.A. Adelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Burgents: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. M. Hussain: Honoraria (self): Sanofi/Genzyme; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self): Research to Practice; Honoraria (self): Aptitude Health; Honoraria (self): Epics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest.
PD-L1 is overexpressed by dendritic cells of mCRPC patients (pts) progressing on androgen receptor antagonist therapy. Anti-PD-1 agents lead to infrequent but durable responses. We tested the hypothesis that dual checkpoint blockade of CTLA-4 with tremelimumab (T) and PD-L1 with durvalumab (D) enhances immune mediated activity in mCRPC.
In this multicenter randomized phase II study, mCRPC pts (measurable disease, prior abiraterone and/or enzalutamide, no more than one taxane for mCRPC) were randomized to D 1500mg IV Q4 weeks +/- 4 doses of T 75mg IV. The primary endpoint was ORR (RECIST1.1 and iRECIST) using a Simon 2-stage design. Key secondary endpoints were PSA response rate (RR) and time to progression (TTP). A treatment arm would be considered of interest if ≥ 4 ORs (null 5% or less, alt 20% or more). Correlative testing was done for PD-L1/CD8 IHC on mandatory tumour biopsies and 74-gene panel (∼1Mb) sequencing of plasma cell-free DNA (cfDNA) both collected at baseline.
52 pts were enrolled: median age 70 yrs (50-83), ECOG 0/1 (13/39 pts), taxane for CRPC (25 pts/48%). Table below shows details of responses. In stage 1, 13 pts were randomized to D with 0% ORR. D+T advanced to stage 2 with a total of 39 pts enrolled who received a median of 3 cycles (1-27). D+T related AEs were mainly grade 2 or less: fatigue (46%), anorexia (28%), rash (24%), diarrhea (23%), nausea/vomiting (21/18%) and thyroid dysfunction (15%). Most common grade 3/4 AEs: LFTs (8%) and diarrhea (8%). Six pts discontinued treatment due to AEs. There were no grade 5 AEs. There were six ORs (16% (95% CI: 6-32); OR median duration not reached, longest ongoing 25mos+ with PSA < 0.2 ng/ml); all six remain on D, and pain improved in three of four pts. Correlation with full cfDNA panel to be presented. LBA51Durvalumab Durvalumab + Tremelimumab ORR 0% (95% CI, 0-25%) 0/13 16% (95% CI, 6-32%) 6/37 PD-L1 ≥1% 0/3 5/13 (38%) <1% 0/9 1/19 (5%) TMB , 11 mts/Mb ctDNA ≥ 0/1 1/2 (50%) < 0/8 4/30 (13%) CD8 density median ≥ 0/5 5/16 (31%) < 0/7 1/14 (7%) PSA RR 0% (0-25%) 0/13 16% (6-32%) 6/37 TTP, median (95% CI), mos 2.1 (1.4, 2.6) 2.6 (1.8, 2.8)
Based on prespecified criteria, D did not show sufficient clinical activity, but further studies incorporating patient selection by biomarkers are warranted for D+T.
NCT02788773.
Canadian Cancer Trials Group (CCTG).
AstraZeneca.
S.J. Hotte: Research grant / Funding (institution): AstraZeneca. E. Winquist: Honoraria (self): AstraZeneca. K.N. Chi: Advisory / Consultancy: AstraZeneca. S. Sridhar: Advisory / Consultancy: AstraZeneca. U. Emmenegger: Research grant / Funding (institution): AstraZeneca. C. Canil: Advisory / Consultancy: AstraZeneca. A.R. Hansen: Research grant / Funding (institution): AstraZeneca. L.K. Seymour: Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.
The antitumor activity of programmed death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibition alone is limited in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Combining immunotherapy with standard-of-care chemotherapy could improve outcomes in mCRPC. We report interim analysis results for the nivolumab + docetaxel (NIVO+DOCE) treatment arm from CheckMate 9KD.
CheckMate 9KD is a phase II study of NIVO in combination with DOCE, rucaparib, or enzalutamide. Eligible pts had confirmed metastatic adenocarcinoma of the prostate, ongoing androgen deprivation therapy, and evaluable tumor biopsy. Pts assigned to NIVO+DOCE (chemotherapy-naïve and received ≤2 prior second-generation hormonal therapies) received NIVO 360 mg every 3 weeks + DOCE 75 mg/m2 every 3 weeks + prednisone 5 mg twice daily for ≤10 cycles followed by NIVO 480 mg every 4 weeks alone until disease progression or unacceptable toxicity (up to 2 years). Coprimary endpoints were objective response rate (ORR) and prostate-specific antigen response rate (PSA-RR; defined as ≥ 50% PSA reduction from baseline). Secondary endpoints included radiographic progression-free survival (rPFS), and safety/tolerability in all treated pts. Association of biomarkers with efficacy was an exploratory endpoint.
This interim analysis included 41 pts in the NIVO+DOCE arm with a minimum follow-up of 28 weeks, of whom 19 (46.3%) had measurable disease. At the time of the analysis, 24 (58.5%) had discontinued study treatment. ORR in pts with measurable disease was 36.8% (95% confidence interval [CI], 16.3–61.6) with 1 complete response and 6 partial responses. Confirmed PSA-RR was 46.3% (95% CI, 30.7–62.6). Median rPFS was 8.2 months (95% CI, 6.6–not estimable). The 6-month rPFS rate was 71.5%. Any-grade and grade 3/4 treatment-related adverse events occurred in 92.7% and 48.8% of pts, respectively. Associations of biomarkers are also evaluated.
The combination of NIVO+DOCE showed encouraging clinical activity in pts with mCRPC, with a safety profile consistent with those of the individual agents. A phase III trial is warranted to further evaluate NIVO+DOCE in mCRPC.
NCT03338790.
Professional medical writing assistance was provided by Nicolette Belletier, PhD, of Parexel, and funded by Bristol-Myers Squibb.
Bristol-Myers Squibb.
Bristol-Myers Squibb and Ono Pharmaceutical Company Limited.
K. Fizazi: Advisory / Consultancy: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Orion. A. Rezazadeh Kalebasty: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AZ; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Macrogenics; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Beyond Spring; Research grant / Funding (institution): Bioclin/Rainier Therapeutics; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Bavarian; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Seattle Genetics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Shareholder / Stockholder / Stock options: ECOM; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Speaker Bureau / Expert testimony: Amgen; Travel / Accommodation / Expenses: Prometheus Labs. J.C. Vazquez Limon: Non-remunerated activity/ies, Personal Fees and non-financial support: AstraZeneca; Non-remunerated activity/ies, Non-financial support: Merck; Non-remunerated activity/ies, Personal fees: Roche; Non-remunerated activity/ies, Personal fees: Bristol-Myers Squibb. A.J. Armstrong: Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer/Astellas; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Byer; Research grant / Funding (institution): Constellation; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Clovis. B. Sharkey: Full / Part-time employment: Bristol-Myers Squibb. A. Saci: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. X. Wang: Full / Part-time employment: Bristol-Myers Squibb. M. Ciprotti: Full / Part-time employment: Bristol-Myers Squibb. P. Sathyanarayana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Bellicum; Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Endocyte ; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Innocrin; Advisory / Consultancy, Research grant / Funding (institution): Johnson and Johnson; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Millineum; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Progenics; Research grant / Funding (institution): Roche Labatories; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): Sotio; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Tyme Pharmaceuticals. R.K. Pachynski: Advisory / Consultancy, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony: Dendreon; Advisory / Consultancy: EMD Serono/Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genomic Health; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy: Jounce Therapeutics. C. Drake: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Compugen; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Astellas Medivation; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tizona Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: F-Star; Advisory / Consultancy, Shareholder / Stockholder / Stock options: KLEO; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Harpoon; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Shattuck Labs; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Werewolf; Advisory / Consultancy: Genocea; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy, Licensing / Royalties: Amplimmune; Advisory / Consultancy, Licensing / Royalties: BMS; Advisory / Consultancy: EMD. All other authors have declared no conflicts of interest.
PD-1 inhibition (α-PD-1) can lead to deep, durable responses in mCRPC, but only in a minority of patients (pts). We previously reported 5 (18%) responders among 28 pts. No marker has been shown to universally predict response. Analysis of fecal microbiota from pts with epithelial cancers showed an association between elevated
30 pts with mCRPC progressing on Enz received α-PD-1 pembrolizumab 200 mg IV every 3 weeks for 4 doses with continued Enz. Prior chemotherapy for mCRPC was prohibited. The primary endpoint was the proportion of pts with a prostate-specific antigen (PSA) decline ≥ 50%. The secondary endpoints were objective response, PSA progression-free survival (PFS), radiographic PFS, overall survival (OS) and correlative studies.
Four of 30 (13%) achieved a PSA reduction ≥ 50%. Six of 24 (25%) pts with measurable disease responded radiographically. After median follow up of 17.4 months (mos), median PSA PFS was 5.57 mos (95%CI: 3.48-8.06). Median OS was 17.25 mos (95% CI: 7.71-17.68). Of 27 pts evaluable for radiographic PFS, 17 (63%) have progressed; median radiographic PFS was 5.26 mos (95% CI: 2.6-11.2). Eight pts had immune related adverse events. Single cell analysis revealed that immune cells represent an average 0.5% of cells in tumor biopsies. Single cell transcriptomic analysis prior to α-PD-1 in 12 pts revealed enrichment in a CD8+ exhausted T cell population (p < 0.0003) in pts who responded to α-PD-1. Fourteen pts had baseline fecal sample. Responders by PSA and/or imaging had significantly lower abundance of A. muc by quantitative PCR (p < 0.022).
Using single cell RNA sequencing, we reveal a T-cell signature associated with response, an observation not possible at the bulk transcriptome level. Responders had lower levels of fecal A. muc than non-responders, suggesting markers of α-PD-1 response in mCRPC may be different than in other cancer types.
NCT02312557.
Julie N Graff.
Merck Sharp & Dohme.
J.N. Graff: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas/Pfizer. A.E. Moran: Research grant / Funding (institution): Merck Sharp & Dohme. J.J. Alumkal: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Janssen Biotech; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Zenith Epigenetics Ltd; Research grant / Funding (institution): Gilead Sciences Inc. R.C. Bergan: Leadership role, Licensing / Royalties, Full / Part-time employment: Third Coast Therapeutics. T.M. Beer: Research grant / Funding (institution): Alliance Foundation Trials; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Corcept Therapeutics; Research grant / Funding (institution): Endocyte Inc; Research grant / Funding (institution): Janssen Research & Development; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): OncoGenex; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Theraclone Sciences/OncoResponse; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Janssen Biotech; Honoraria (self), Advisory / Consultancy: Janssen Japan; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.
PSMA is overexpressed in PC with limited expression in other organs. PC is radiosensitive with dose-response. Dose-fractionation allows delivery of higher total dose per cycle, may result in less radioresistance due to repopulation compared with doses 6-12 wks apart. Initial Ph I safety results of the dose-escalation portion of this study [ESMO 2018] were without DLT at all dose levels.
Entry criteria: progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2. No preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15. In the Ph I dose-escalation cohort, men received 7.4 to 22 GBq. In Ph II, a Simon 2 stage design enrolled pts at the 22.2 GBq dose level. Pre- and post-treatment 68Ga-PSMA11 PET/CT and post-treatment 177Lu-PSMA-617 imaging was performed in addition to standard serial CT and bone scans. Cellsearch CTC count at baseline and 12 wks.
44 men (29 in Ph I, 15 in Ph II; total 21 at 22.2 GBq) with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% >1 prior potent AR therapy, 27% with Ra223, 30% sip-T, 5% 177Lu-J591; 66% Halabi poor risk, 30% intermed risk. With follow up ongoing, 61% with >50% PSA decline (71.4% at 22.2 GBq), median overall survival 16 months (95% CI 11-NR). Of 26 with paired CTC counts, 57.7% decreased, 7.7% stable, 34.6% increased; 34.6% converted from detectable to undetectable at 12 weeks). 61.4% with all grade xerostomia, 29.5% fatigue, 25% thrombocytopenia, 25% anemia, 25% pain, 15.5% nausea. While not required for eligibility, all pts had some PSMA uptake in at least 1 site on PSMA PET, with 2.2% highest lesion SUV < liver SUV, 4.5% 1-2.5x, 13.6% 2.5-5x, and 79.5% highest lesion SUV > 5x liver.
A single fractionated cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe, with encouraging early efficacy signals, even without selection for PSMA expression by imaging. A trend for dose-response was observed.
NCT03042468.
Well Cornell Medicine.
Weill Cornell Medicine, Prostate Cancer Foundation, US Department of Defense, US National Institutes of Health, Endocyte.
S.T. Tagawa: Advisory / Consultancy, Research grant / Funding (institution): Endocyte. H. Beltran: Advisory / Consultancy: Endocyte. S. Vallabhajosula: Research grant / Funding (institution): Endocyte; Full / Part-time employment: NCM USA. O. Sartor: Research grant / Funding (institution): Endocyte. All other authors have declared no conflicts of interest.
STAMPEDE previously reported that adding upfront docetaxel (Doc) improved overall survival (OS) for locally advanced and metastatic patients (pts) starting long-term androgen deprivation therapy (ADT). We report the long-term outcomes for M0 pts using metastatic progression-free survival (mPFS) as primary outcome, previously shown to be a surrogate for OS in M0 pts.
Standard-of-care (SOC) was ADT +/- radical radiotherapy (RT) to the prostate. 460 SOC and 230 SOC+Doc pts were recruited with 2:1 randomised stratified allocation. Standard survival intention-to-treatment analysis methods used Cox regression models adjusted for all stratification factors, with emphasis on restricted mean survival time (RMST) for non-proportional (non-PH) hazards. There was 70% power (2-sided α = 0.05) to detect HR = 0.70 for mPFS (= new metastases, skeletal related events or PCa death). Secondary outcome measures included failure free survival (FFS) and progression free survival (PFS = mPFS or locoregional progression).
Median follow-up was ∼6.5yr compared to ∼3.5yr when last reported, with 142 mPFS events (a 54% increase) on SOC. There was no good evidence of an advantage of SOC+Doc over SOC on mPFS (HR = 0.89, 95% CI 0.66-1.19, P = 0.425); with 5yr mPFS 82% in SOC+Doc vs. 77% SOC. Secondary outcomes showed evidence that SOC+Doc improved FFS (HR = 0.70, 95% CI 0.55-0.88, P = 0.002) and PFS (non-PH P = 0.033, RMST difference=5.8 months, 95% CI 0.5-11.2, P = 0.031). There was no good evidence of a benefit of SOC+Doc on OS (125 SOC deaths; HR = 0.88, 95% CI 0.64-1.21, P = 0.442). There was no evidence that SOC+Doc increased late toxicity compared to SOC: after 1yr, G3-5 toxicity reported for 29% SOC and 30% SOC+Doc. The impact of SOC RT (nominated prior to randomisation) with and without SOC+Doc will also be detailed by subgroup.
There is robust evidence SOC+Doc improves FFS and PFS (which we have previously shown increases Quality Adjusted Life Years). There is however no good evidence that this translates into benefit for longer-term outcomes (OS or mPFS). The benefits of upfront SOC+Doc for improved FFS and PFS with no excess late toxicity may contribute to treatment discussions.
NCT00268476.
University College London.
Cancer Research UK; Sanofi; MRC; Astellas; Clovis; Janssen; Novartis; Pfizer.
N.D. James: Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen. N.W. Clarke: Advisory / Consultancy: Janssen. G. Attard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Medivation; Advisory / Consultancy: Novartis; Advisory / Consultancy: Millennium Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Abbott Laboratories; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Essa Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bayer Healthcare Pharmaceuticals; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sanofi-Aventis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Arno Therapeutics; Research grant / Funding (self): Innocrin Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen; Advisory / Consultancy: Veridex; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche/Ventana; Advisory / Consultancy, Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), I was an employee of the ICR, where abiraterone acetate was developed, up to 8 January 2018. : The Institute of Cancer Research (ICR). W. Cross: Speaker Bureau / Expert testimony: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer. D. Dearnaley: Research grant / Funding (institution), Financial Support for Trial Recruitment: UK National Institute for Health Research Clinical Research Network (NIHR CRN); Research grant / Funding (institution): The Institute of Cancer Research (ICR); Research grant / Funding (self), C46/A3976, C46/A10588 and C33589/A19727. : Cancer Research UK; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Sandoz; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen. R. Jones: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. M.D. Mason: Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Bayer. C. Parker: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self): AAA; Speaker Bureau / Expert testimony: Janssen. M.K.B. Parmar: Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Sanofi. M.R. Sydes: Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Janssen; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Sanofi. All other authors have declared no conflicts of interest.
We previously reported that treatment with enzalutamide (ENZA) rather than an older non-steroidal anti-androgen (NSAA: bicalutamide, nilutamide, or flutamide), resulted in longer overall survival when added to standard first-line treatment, with or without concurrent early docetaxel, in mHSPC (hazard ratio 0.67, 95% CI 0.52 to 0.86, p = 0.002, NEJM 2019). Here we report effects on HRQL.
HRQL was measured with the EORTC QLQ-C30 and PR25 at weeks 0, 4, 12, and then 12-weekly until clinical progression. We used mixed models for repeated measures to calculate the least squares mean difference (LSMD), 95% CI, and p-value for comparisons of the randomly assigned groups for all assessments from week 4 to 156. For each analysis of deterioration-free survival, the endpoint was defined a-priori as the earliest of death, clinical progression, cessation of study treatment, or a 10-point worsening from baseline (minimum clinically important difference on scales scored from 0 to 100) in the pertinent HRQL sub-scale: physical functioning (PF), global health and quality of life (GHQL), cognitive functioning (CF), and fatigue; p-values were based on the log-rank test.
Completion of HRQL forms in 1016 men with a baseline assessment of HRQL (1125 randomised) ranged from 94% at week 12 to 78% at week 156. Random assignment to ENZA v NSAA was associated with modest impairments (LSMD, 95% CI) from week 4 to 156 in fatigue (5.0, 3.3 to 6.7, p < 0.0001), CF (3.9, 2.4 to 5.4, p < 0.0001), and PF (2.5, 1.2 to 3.8, p = 0.0002), but not GHQL (1.1, -0.4 to 2.6, p = 0.16). Deterioration-free survival rates at 3 years favoured ENZA over NSAA for GHQL (32% v 18%, p < 0.0001), CF (33% v 21%, p = 0.0003), and PF (31% v 22%, p = 0.001), but not fatigue (26% v 18%, p = 0.1). The effects of ENZA on HRQL were relatively stable over time and unaffected by treatment with concurrent early docetaxel.
The addition of ENZA maintained GHQL and improved deterioration-free survival because early impairments in specific aspects of HRQL were insufficient to outweigh the subsequent benefits of delayed clinical progression.
ACTRN12614000110684, NCT02446405; EUCTR2014-003190-42-IE.
ANZUP Cancer Trials Group and the NHMRC Clinical Trials Centre, University of Sydney.
Astellas Pharma.
M.R. Stockler: Research grant / Funding (institution): Astellas; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Bayer. A.J. Martin: Research grant / Funding (institution): Astellas. I.D. Davis: Research grant / Funding (institution): Astellas. K.N. Chi: Research grant / Funding (institution): Astellas. S. Chowdhury: Research grant / Funding (institution): Astellas. L.G. Horvath: Research grant / Funding (institution): Astellas. N.J. Lawrence: Research grant / Funding (institution): Astellas. G.M. Marx: Research grant / Funding (institution): Astellas. J. Mc Caffrey: Research grant / Funding (institution): Astellas. R. McDermott: Research grant / Funding (institution): Astellas. S.A. North: Research grant / Funding (institution): Astellas. F. Parnis: Research grant / Funding (institution): Astellas. D.W. Pook: Research grant / Funding (institution): Astellas. M.N. Reaume: Research grant / Funding (institution): Astellas. S.K. Sandhu: Research grant / Funding (institution): Astellas. T.H. Tan: Research grant / Funding (institution): Astellas. A. Thomson: Research grant / Funding (institution): Astellas. R. Zielinski: Research grant / Funding (institution): Astellas. C.J. Sweeney: Research grant / Funding (institution): Astellas. All other authors have declared no conflicts of interest.
Prostate radiotherapy (PRT) with androgen deprivation therapy (ADT) is now recommended as a first line option for de-novo low burden metastatic prostate cancer. In the STAMPEDE “M1|RT comparison” metastatic burden was a determinant of benefit, based on pre-specified prognostic criteria. We have now performed exploratory analyses of metastases as defined by site and number to improve prediction of treatment benefit from PRT.
Patients (pts) randomized to the ADT (± docetaxel) vs PRT + ADT (± docetaxel) were studied. Metastatic site, distribution and number were evaluated based on conventional imaging and used to explore treatment effects to refine the metastatic burden definition. Results focused on the trial’s key outcome measures: overall (OS) & failure-free survival (FFS), analysed using standard survival analysis methods. HR < 1 indicates benefit associated with PRT + ADT (±docetaxel) over ADT (±docetaxel).
Following exclusions (imaging unavailable for central review, n = 122), 1939 pts randomized in “M1|RT comparison” were included. Of these, 181 pts had only lymph node (LN) mets, 1587 had bone (±LN) mets and 171 had other visceral mets (±bone/LN). Baseline characteristics such as age (median 68 years), PSA (median 98 ng/ml) were balanced between the arms. In LN only pts, PRT improved OS (HR = 0.62, 95%CI 0.35-1.09) & FFS (HR = 0.64, 95%CI 0.43-0.96). In bone (±LN) pts with <4 bone mets regardless of bone met location, PRT improved OS (HR = 0.65, 95% CI 0.47 – 0.92) & FFS (HR = 0.58, 95% CI 0.46 – 0.73). No such evidence of benefit was found in pts with visceral mets (OS: HR = 0.92, 95%CI 0.58 – 1.45) or bone (±LN) pts with ≥4 bone mets (OS: HR = 1.11, 95%CI 0.92 – 1.33). In the refined low met burden subgroup of pts with only LN or < 4 bone mets (±LN), PRT improved OS (HR = 0.62, 95%CI 0.46 – 0.83) & FFS (HR = 0.57, 95%CI 0.47 – 0.70). Within the low met burden subgroup there was no evidence of heterogeneity in OS & FFS (all interaction p-value >0.1) for baseline factors such as age, N stage, Gleason score, RT schedule or docetaxel use.
Prostate RT + ADT (± docetaxel) improved OS & FFS in pts with only LN or < 4 bone mets (±LN) regardless of location.
NCT00268476.
Medical Research Council-Clinical Trials Unit and University of Manchester.
Has not received any funding.
All authors have declared no conflicts of interest.
Compared with PBO, addition of APA to ADT significantly improved radiographic progression-free survival (rPFS [HR, 0.48; 95% CI, 0.39-0.60; p < 0.0001]), and overall survival (OS [HR, 0.67; 95% CI, 0.51-0.89; p = 0.0053]) in pts with mCSPC (TITAN Study; Chi KN et al. NEJM 2019). In this analysis, we evaluated pain, fatigue, and overall health-related quality of life (HRQoL) of pts in TITAN.
mCSPC pts (N = 1052) were randomized 1:1 to APA (240 mg QD; n = 525) or PBO (n = 527). All pts received ADT. Pts were stratified by Gleason score at diagnosis (≤ 7 vs > 7), region (North America vs European Union vs other countries), and prior docetaxel use (yes vs no). PROs were assessed using the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and Euro QoL Group EQ-5D-5L. BPI and BFI were completed for 7 consecutive days (D) (D -6 plus D1 of each cycle [C] visit), then at Months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed C1 through C7, then every other C through end of treatment (tmt), and at Months 4, 8, and 12 in follow-up. Analyses included descriptive statistics and mean change from baseline using mixed model of repeated measures.
Pts were relatively asymptomatic at baseline: on 0-10 severity scales, median pain scores were 1.14 (APA) and 1.00 (PBO), and median fatigue scores were 1.29 (APA) and 1.43 (PBO). Pt experience of pain and fatigue (both intensity and interference) was similar between groups for the duration of tmt. For the majority of pts in both arms, pain and fatigue remained stable or improved during tmt, with greater improvements observed in pts with higher baseline severity scores. FACT-P total score and EQ-5D-5L data showed similar maintenance of overall HRQoL in both arms. Similar tolerability was experienced between groups based on the FACT-P single item side effects bother question.
The addition of APA to ADT maintained overall HRQoL while significantly improving OS and rPFS in mCSPC pts.
NCT02489318.
Chris R. Prostko, PhD, of Parexel.
Janssen Research & Development.
Janssen Research & Development.
N. Agarwal: Advisory / Consultancy: Argos Therapeutics; AstraZeneca; Bayer; Bristol-Myers Squibb; Clovis Oncology; Eisai; EMD Serono; Exelixis; Foundation One Inc; Genentech/Roche; Lilly; Medivation/Astellas; Merck; Nektar; Novartis; Pfizer; Research grant / Funding (institution): Active Biotech; Amgen; AstraZeneca; Bavarian Nordic; Bayer; BN ImmunoTherapeutics; Bristol-Myers Squibb; Calithera Biosciences; Celldex; Eisai; Exelixis; Genentech; GlaxoSmithKline; Immunomedics; Janssen; Medivation; Merck; Newlink Genetics. K. McQuarrie: Full / Part-time employment: Janssen; Shareholder / Stockholder / Stock options: Johnson & Johnson. A. Bjartell: Shareholder / Stockholder / Stock options: Glactone Pharma AB. S. Chowdhury: Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self): Novartis; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Bayer; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Research grant / Funding (institution): Sanofi/Aventis. B.H. Chung: Honoraria (self), Advisory / Consultancy: Astellas (Korea); Honoraria (self), Advisory / Consultancy: Ipsen (Korea); Honoraria (self): JW Pharma (Korea); Honoraria (self): Takeda (Korea); Advisory / Consultancy: Janssen (Korea); Advisory / Consultancy: Handok (Korea); Research grant / Funding (self): Janssen (USA); Research grant / Funding (self): Bayer (Germany); Research grant / Funding (self): Pfizer (USA); Research grant / Funding (self): AstraZeneca (UK). Juárez Soto: Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Coloplast; Research grant / Funding (self): Bayer. A. Merseburger: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen-Cilag; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas. H. Uemura: Honoraria (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self): Astellas; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: AstraZeneca. R. Given: Shareholder / Stockholder / Stock options: Multiple companies as individual stock and within mutual funds; Honoraria (self): HealthTronics; Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Research grant / Funding (self): Ferring; Research grant / Funding (self): Veru; Research grant / Funding (self): Medivation; Research grant / Funding (self): Clovis. B. Miladinovic: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. L. Dearden: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. K. Deprince: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. V. Naini: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. A. Lopez-Gitlitz: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: ESSA; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lilly/ImClone; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tokai Pharmaceuticals. All other authors have declared no conflicts of interest.