Background

Adding abiraterone acetate + prednisone (AAP) & adding docetaxel + prednisone (DocP) to standard of care (SOC) each improved survival vs SOC in STAMPEDE: a multi-arm multi-stage platform randomised controlled protocol recruiting pts with high risk locally advanced or metastatic PCa starting long-term ADT. We share the first direct, randomised data of SOC+AAP or SOC+DocP using a STAMPEDE subset.

Methods

Recruitment to the “DocP comparison” & “AAP comparison” overlapped Nov2011 - Jan2014. SOC was long term ADT or 2+yr ADT with RT (for some M0). Stratified randomisation allocated pts 2:1:2 to SOC: or SOC + Doc 75mg/m2 3-weekly x6 + P 5mg twice daily: or SOC + AA 1000mg + P 5mg daily. AAP duration depended on stage & intent for radical RT. Primary outcome measure was death from any cause. Analyses used Cox proportional hazards & flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison; power is limited, but is indicative of the likely magnitude of difference: HR < 1 favours SOC+AAP, HR > 1 favours SOC+DocP. All confidence intervals (CI) are 95%.

Results

566 pts were contemporaneously randomised: 189 SOC+DocP (the last of 592 SOC+DocP pts) & 377 SOC+AAP (the first of 960 SOC+AAP pts). Groups were well balanced with 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO PS 0; median age 66yr & PSA 56ng/ml. At median follow up 4 yr, there were 149 deaths (45 SOC+Doc, 111 SOC+AAP): survival HR 1.16 (0.82-1.65); failure free survival HR = 0.51 (0.39-0.67); progression free survival HR 0.65 (0.48-0.88); metastases free survival HR 0.77 (0.57-1.03); & SRE HR 0.83 (0.55-1.25). There was no heterogeneity by baseline M0/M1. Grade 3, 4, 5 toxicity was 36%, 13%, 1% SOC+DocP, & 40%, 7%, 1% SOC+AAP. Subsequent treatments varied by arm, with much crossing after progression.

Conclusions

In this direct, randomised, comparative analysis of 2 new standards for HNPC, FFS & PFS clearly favoured SOC+AAP &, with less certainty, MFS & SRE favoured SOC+AAP & survival SOC+Doc. Worst toxicity grade was similar. Drug availability may drive treatment choice. Published STAMPEDE data also contribute to a network MA (#2871).

Clinical trial identification

NCT00268476

Legal entity responsible for the study

Medical Research Council

Funding

Cancer Research UK, Medical Research Council, Janssen; Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi-Aventis

Disclosure

M.R. Sydes: Grants and non-financial support from Janssen, Astellas, Clovis Oncology, Novartis, Pfizer, Sanofi-Aventis M.D. Mason: Personal fees and other from Sanofi, personal fees from Bayer, other from Janssen, outside the submitted work N.W. Clarke: Personal fees from Janssen Pharmaceuticals, during the conduct of the study; personal fees from Janssen Pharmaceuticals, outside the submitted work; . D. Dearnaley: Financial Support for Trial Recruitment M. Russell: Dr. Russell reports from Jannsen-Cilag, outside the submitted work. R. Jones: Personal fees and non-financial support from Janssen, grants, personal fees and other from Astellas, outside the submitted work. J. de Bono: Employee of the ICR which has a commercial interest in abiraterone. Has served on Janssen Advisory Board as a consultant. S. Gillessen: Bayer, CureVac, Janssen Cilag, Dendreon Corp, Astellas, Millennium Pharmaceuticals, Orion, Sanofi, MaxiVax SA, AAA, Bristol-Myers Squibb, Ferring, Roche, Innocrin Pharmaceuticals, Nektar Therapeutics, ProteoMedix. S. Chowdhury: Personal fees from Janssen Paharmaceutical, outside the submitted work; . J. Lester: Personal fees, non-financial support and other from Janssen, personal fees, non-financial support and other from Astellas, outside the submitted work. M.K. Parmar: Jansenn: Unrestricted grant to contribute to this comparison of STAMPEDE which supports the protocol overall, plus abiraterone and distribution. N.D. James: Grants, personal fees and non-financial support from Janssen, Astellas, Sanofi, Novartis during the conduct of the study; grants and non-financial support from Clovis Oncology, Pfizer All other authors have declared no conflicts of interest.

Background

In the LATITUDE study, treatment with ADT+AA+P significantly improved overall survival and delayed disease progression in pts with newly diagnosed, high-risk, metastatic castration-naïve prostate cancer (mCNPC). In this analysis we evaluated the impact of ADT+AA+P on PROs, including symptom and health-related quality of life (HRQoL) measures.

Methods

1199 mCNPC pts were randomized 1:1 to ADT + AA+P or ADT + placebos (PBOs). Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EQ-5D-5L questionnaires were administered at baseline (BL), Day 1 of Cycles (C) 2-13, then every 2 months until treatment discontinuation (TD). EQ-5D-5L were performed every 4 months until 12 months after TD. Time to event and repeated measures analyses on changes from baseline were conducted.

Results

Questionnaire compliance rate was high at ≥ 90%. Compared to ADT+PBOs, the ADT+AA+P arm had significant delayed time to pain and fatigue intensity and interference progression (Table). FACT-P assessments demonstrated significant delay in degradation for the total score and symptom subscales for the ADT+AA+P arm (Table). Repeated measures analyses showed maintenance or improvement from BL for the ADT+AA+P arm compared to the ADT+PBOs arm, with significant differences emerging as early as C2. Significant improvement from BL in EQ-5D VAS for general health status and health utility scores occurred as early as C5 and was maintained throughout the study.

Conclusions

Compared with ADT+PBOs, treatment with ADT+AA+P consistently demonstrated improvement across multiple PRO measures, with statistically significant improvement in HRQoL and delays in progression of pain fatigue intensity and interference, and functional decline. Results for PROs were consistent with improvements in clinical outcomes.

Clinical trial identification

EudraCT: 2012-002940-26 NCT01715285

Legal entity responsible for the study

Janssen Research & Development

Funding

Janssen Research & Development

Disclosure

K. Chi: Consulting/Advisory Role: Janssen Research Funding: Janssen A. Protheroe: Consulting/Advisory Role: IPSEN, Bayer, Roche, BMS Research Funding: Merck Travel, Accommodations, Expenses: BMS A. Rodriguez Antolin: Consulting/Advisory Role: Astellas, Janssen, Bayer Speaker's Bureau: Astellas, Janssen Travel, Accommodations, Expenses: Astellas, IPSEN Pharma H. Suttmann: Honoraria, Consulting/Advisory Role, Research Funding: Astellas, Bayer Health Care, Bristol-Myers-Squibb, Ipsen, Janssen-Cilag, Medac, Santorin-Aventis N. Matsubara: Consulting/Adisory Role: MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi, Taiho, Takeda, Chugai, Novartis, Bayer, Yakuhin, Pfizer Japan, Merck, Serono, Janssen - Research Funding: Shionogi, Bayer, Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD Z-Q. Ye: Consulting/Adisory Role: MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi, Taiho, Takeda, Chugai, Novartis, Bayer, Yakuhin, Pfizer Japan, Merck, Serono, Janssen - Research Funding: Shionogi, Bayer, Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD T. Li, P. De Porre, J. Martin: Employment at Janssen Research and Development Stock Ownership of Johnson & Johnson K. McQuarrie, B. Jia, M.B. Todd: Employment at Janssen Research and Development Stock Ownership of Johnson & Johnson K. Fizazi: Honoraria, Consulting/Advisory Role: Astellas, Bayer, Clovis, Curevac, Genentech, Janssen, Orion, Sanofi All other authors have declared no conflicts of interest.

Disclosure

K. Chi: Consulting/Advisory Role: Janssen Research Funding: Janssen A. Protheroe: Consulting/Advisory Role: IPSEN, Bayer, Roche, BMS Research Funding: Merck Travel, Accommodations, Expenses: BMS A. Rodriguez Antolin: Consulting/Advisory Role: Astellas, Janssen, Bayer Speaker\'s Bureau: Astellas, Janssen Travel, Accommodations, Expenses: Astellas, IPSEN Pharma H. Suttmann: Honoraria, Consulting/Advisory Role, Research Funding: Astellas, Bayer Health Care, Bristol-Myers-Squibb, Ipsen, Janssen-Cilag, Medac, Santorin-Aventis N. Matsubara: Consulting/Adisory Role: MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi, Taiho, Takeda, Chugai, Novartis, Bayer, Yakuhin, Pfizer Japan, Merck, Serono, Janssen - Research Funding: Shionogi, Bayer, Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD Z-Q. Ye: Consulting/Adisory Role: MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi, Taiho, Takeda, Chugai, Novartis, Bayer, Yakuhin, Pfizer Japan, Merck, Serono, Janssen - Research Funding: Shionogi, Bayer, Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD T. Li, P. De Porre, J. Martin: Employment at Janssen Research and Development Stock Ownership of Johnson & Johnson K. McQuarrie, B. Jia, M.B. Todd: Employment at Janssen Research and Development Stock Ownership of Johnson & Johnson K. Fizazi: Honoraria, Consulting/Advisory Role: Astellas, Bayer, Clovis, Curevac, Genentech, Janssen, Orion, Sanofi All other authors have declared no conflicts of interest.

Background

HrPC pts with PSA relapse after local therapy may have a poor prognosis and AS may be a therapeutic option. D+AS is standard of care in hormone-naive metastatic PC. We evaluated the benefit of D+AS in HrPC pts with PSA relapse after RP and/or RT.

Methods

Multicenter, randomized phase 3 study (NCT00764166) comparing AS (triptorelin, every 3 months for 1 year) versus AS+D (70 mg/m² Q3W, 6 cycles). To be enrolled, pts needed ≥ 3 rising PSA values >0.2ng/mL (after RP) or > 1ng/mL above nadir (after RT) modified by nadir + 2ng/ml (RTOG-ASTRO Phoenix, 2006) and ≥ 1 of the following criteria: Gleason ≥8, PSA doubling time (PSADT) ≤6 mths, PSA velocity >0.75 ng/mL/year, positive surgical margins (SM), pN1, time from curative therapy to PSA relapse ≤12 months. Pts were stratified on type of local treatment (RP or RT) and PSADT (≤ or > 6 mths). Primary endpoint was PSA-PFS defined by a PSA above 0.2ng/ml and rise ≥ 50% from baseline confirmed by 2 subsequent values. Secondary endpoints were PSA response (decrease ≥50%), radiological progression (rPFS), overall survival (OS) and safety.

Results

between 2003-2007, 250 pts (median age 65 years), were randomized to AS+D (arm A, n = 125) or AS (arm B, n = 125). Local treatment: RP (95 pts, 38%), RT (69 pts, 28%) or RP+RT (86 pts, 34%). Risk factors were as follows: Gleason ≥8: 29%, PSADT≤ 6 mths 54%, PSA velocity >0.75 ng/mL/yr 84%, positive SM 37%, pN1 4%, PSA relapse ≤12 mths 45%. 58% of pts had ≥3 risk factors. Six pts had a PSA >20 ng/ml at baseline. There was no significant difference in PSA response (94% vs 98%), PSA-PFS and rPFS between 2 arms (table). Median OS was not mature. Most common grade ≥3 toxicities in arm A were neutropenia (58%), febrile neutropenia (8%) and hair loss (4%). AS toxicities were mainly grade 2 hot flushes (47%) and depression (11%).Table:

784O

Conclusions

AS+D failed to improve PSA-PFS, rPFS in HrPC pts relapsing PSA after local therapy.

Clinical trial identification

NCT00764166

Legal entity responsible for the study

Stéphane OUDARD, MD, PhD

Funding

Sanofi Aventis

Disclosure

S. Oudard: Honoraria from Sanofi, Novartis, Roche, Ipsen, BMS outside submited work L. Miglianico, E. Sevin, A-C. Hardy Bessard: Fees from Sanofi. C. Chevreau, C. Linassier, S. Culine: Fees from Sanofi, Astellas, Janssen. F. Priou: Fees from Sanofi. P. Beuzeboc: Fees from Sanofis, Astellas, Janssen. G. Gravis: Travel paid by Sanofi, Astellas, Janssen All other authors have declared no conflicts of interest.

Background

Progressive metastatic castrate-resistant prostate carcinoma (mCRPC) is a highly lethal condition. Lutetium-177 (¹⁷⁷Lu)-PSMA617, a radiolabelled small molecule, binds with high affinity to prostate specific membrane antigen (PSMA) enabling beta particle therapy targeted to mCRPC.

Methods

In this phase II prospective trial, 30 pts with PSMA-avid mCRPC who had failed standard therapies received up to 4 cycles of ¹⁷⁷Lu-PSMA617 every 6 weeks. The primary endpoints were PSA and imaging response (PCWG2) and toxicity (CTCAE v4). Other endpoints were quality of life (EORTC QLQ-C30/BM22, BPI), dosimetry, PFS and OS.

Results

All patients were enrolled between 10/2015 and 12/2016 (median age 69 yr, ECOG 1; PSA doubling time 2.2 months) with 3 pts awaiting a final treatment cycle. 87% received prior chemotherapy, 47% cabazitaxel and 83% prior abiraterone and/or enzalutamide. Mean dose was 7.5 GBq (range 4.4 – 8.7 GBq) prospectively adjusted according tumour burden, renal function and weight. At this interim analysis, 17/30 pt (57%) achieved PSA decline >50%, including 11/30 (37%) with decline >80%. In 17 pt with soft tissue disease, objective response (RECIST PR+CR) occurred in 12 pt (71%). Most common adverse events were grade 1 xerostomia (19 pt, 63%) and nausea (15 pt, 50%). Grade 3 or higher hematoxicity occurred in 5 pt (17%); all had baseline thrombocytopenia and were reversible. Following the first cycle of LuPSMA, global health score improved significantly (≥10 points) in 11/30 pt (37%), while in those with bone pain, mean severity score improved significantly (≥ 10 points) in 9/21 pt (43%).

Conclusions

The LuPSMA Phase II trial provides evidence of high response rates and low toxicity with improved QoL and pain reduction in men with mCRPC who have failed conventional therapies.

Clinical trial identification

Australian New Zealand Clinical Trials Registry: ACTRN12615000912583. Universal Trial Number (UTN): U1111-1172-4095.

Legal entity responsible for the study

Peter MacCallum Cancer Centre, Melbourne, Australia

Funding

Investigator-initiated trial. Lutetium-177 (no carrier added) supplied by Australian National Nuclear Research and Development Organisation (ANSTO). PSMA617 supplied by Advanced Biochemical Compounds (ABX).

Disclosure

All authors have declared no conflicts of interest.

Background

Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes and progression to metastatic disease, but no conclusive data are available regarding survival from mCRPC and response to currently approved survival-prolonging therapies (SPT).

Methods

Prospective multicentre observational study of newly diagnosed mCRPC patients with unknown germline mutation status at study entry. Patients were treated at physician-choice’s with either abiraterone, enzalutamide, docetaxel, cabazitaxel or Ra-223. Primary endpoint was to assess the impact or BRCA1, BRCA2, ATM and PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. It required enrolling at least 408 patients and to observe at least 171 deaths to demonstrate a CSS HR of germline mutation carriers (C) vs non-carriers (NC) equal to 3 (α = 0.05 & β = 0.20). Secondary endpoints included the association of those mutations to the response to SPT.

Results

From January 2013 to April 2016, 419 eligible patients from 38 Spanish institutions were enrolled. Identified C were 14 BRCA2, 8 ATM and 4 BRCA1 (6.2%). A non-significant (NS) trend to younger age (median 66.5 vs 71.6 yrs, p = 0.16) was observed in C compared to NC. Median time from ADT initiation to mCRPC in C and NC was 23.7 vs 26.7 m (p = 0.22); in the BRCA2 subgroup was 18 m (p = 0.24). Other baseline characteristics were also NS different between C and NC at 1^st SPT initiation: ECOG 0-1 (92% vs 88%), median PSA (27.9 vs 31.0), bone (96% vs 86%), nodal (48% vs 52%) and visceral (12% vs 16%) metastasis. 1^st SPT in C and NC were a taxane for 63% and 46% for novel AR targeting therapies (ART) for 37% and 53%, respectively. After a median follow-up of 36 m, 207 prostate-cancer deaths were observed. Median CSS from mCRPC was 28.5 m in C vs 36.0 m in NC (p = 0.5), and 17.4 m in the BRCA2 subgroup (p = 0.02). Median CSS and PFS from 1^st taxane in C and NC were 17.3 vs 24.5 m, p = 0.6 (BRCA2 12.8 m, p < 0.01) and 7.8 vs 7.1 m, p = 0.4 (BRCA2 5.7 m, p = 0.3), respectively. CSS and PFS from 1^st ART in C and NC were 25.4 vs 26.6 m, p = 0.9 (BRCA2 27.6 m, p = 0.05) and 8.2 vs 9.4 m, p = 0.8 (BRCA2 5.8 m, p = 0.4), respectively.

Conclusions

When all C considered, non-significant trends to worse CSS from mCRPC, from 1^st taxane and from 1^st ART were observed. Nonetheless, pre-planned subgroup analyses suggest that BRCA2 mutations are associated with significantly worse outcomes.

Clinical trial identification

NCT03075735

Legal entity responsible for the study

Spanish National Cancer Research Centre (CNIO) and Instituto de Investigación Biomédica de Málaga (IBIMA)

Funding

Prostate Cancer Foundation, Fundación CRIS Contra el Cáncer, Fundación Obra Social La Caixa, Instituto de Salud Carlos III

Disclosure

All authors have declared no conflicts of interest.