Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Chris C Parker; Howard Kynaston; Adrian D Cook; Noel W Clarke; Charles N Catton; William R Cross; Peter M Petersen; Rajendra A Persad; Cheryl A Pugh; Fred Saad; John Logue; Heather Payne; Lorna C Bower; Chris Brawley; Mary Rauchenberger; Maroie Barkati; David M Bottomley; Klaus Brasso; Hans T Chung; Peter W M Chung; Ruth Conroy; Alison Falconer; Vicky Ford; Chee L Goh; Catherine M Heath; Nicholas D James; Charmaine Kim-Sing; Ravi Kodavatiganti; Shawn C Malone; Stephen L Morris; Abdenour Nabid; Aldrich D Ong; Rakesh Raman; Sree Rodda; Paula Wells; Jane Worlding; Wendy R Parulekar; Mahesh K B Parmar; Matthew R Sydes; RADICALS investigators

doi:10.1016/S0140-6736(24)00549-X

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Chris C Parker, Howard Kynaston, Adrian D Cook, Noel W Clarke, Charles N Catton, William R Cross, Peter M Petersen, Rajendra A Persad, Cheryl A Pugh, Fred Saad, John Logue, Heather Payne, Lorna C Bower, Chris Brawley, Mary Rauchenberger, Maroie Barkati, David M Bottomley, Klaus Brasso, Hans T Chung, Peter W M ChungRuth Conroy, Alison Falconer, Vicky Ford, Chee L Goh, Catherine M Heath, Nicholas D James, Charmaine Kim-Sing, Ravi Kodavatiganti, Shawn C Malone, Stephen L Morris, Abdenour Nabid, Aldrich D Ong, Rakesh Raman, Sree Rodda, Paula Wells, Jane Worlding, Wendy R Parulekar, Mahesh K B Parmar, Matthew R Sydes^*, RADICALS investigators

^*Corresponding author for this work

Abstract

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.

METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.

FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.

INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.

FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Original language	English
Journal	Lancet
Volume	403
Issue number	10442
Pages (from-to)	2416-2425
Number of pages	10
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(24)00549-X
Publication status	Published - 2024

Keywords

Aged
Androgen Antagonists/therapeutic use
Anilides/therapeutic use
Combined Modality Therapy
Drug Administration Schedule
Gonadotropin-Releasing Hormone/agonists
Humans
Male
Middle Aged
Nitriles/therapeutic use
Oligopeptides/administration & dosage
Prostate-Specific Antigen/blood
Prostatectomy
Prostatic Neoplasms/pathology
Tosyl Compounds/therapeutic use

Access to Document

10.1016/S0140-6736(24)00549-X

Fingerprint

Dive into the research topics of 'Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial'. Together they form a unique fingerprint.

Cite this

Parker, C. C., Kynaston, H., Cook, A. D., Clarke, N. W., Catton, C. N., Cross, W. R., Petersen, P. M., Persad, R. A., Pugh, C. A., Saad, F., Logue, J., Payne, H., Bower, L. C., Brawley, C., Rauchenberger, M., Barkati, M., Bottomley, D. M., Brasso, K., Chung, H. T., ... RADICALS investigators (2024). Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial. Lancet, 403(10442), 2416-2425. https://doi.org/10.1016/S0140-6736(24)00549-X

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial. / Parker, Chris C; Kynaston, Howard; Cook, Adrian D et al.
In: Lancet, Vol. 403, No. 10442, 2024, p. 2416-2425.

Research output: Contribution to journal › Journal article › Research › peer-review

Parker, CC, Kynaston, H, Cook, AD, Clarke, NW, Catton, CN, Cross, WR, Petersen, PM, Persad, RA, Pugh, CA, Saad, F, Logue, J, Payne, H, Bower, LC, Brawley, C, Rauchenberger, M, Barkati, M, Bottomley, DM, Brasso, K, Chung, HT, Chung, PWM, Conroy, R, Falconer, A, Ford, V, Goh, CL, Heath, CM, James, ND, Kim-Sing, C, Kodavatiganti, R, Malone, SC, Morris, SL, Nabid, A, Ong, AD, Raman, R, Rodda, S, Wells, P, Worlding, J, Parulekar, WR, Parmar, MKB, Sydes, MR & RADICALS investigators 2024, 'Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial', Lancet, vol. 403, no. 10442, pp. 2416-2425. https://doi.org/10.1016/S0140-6736(24)00549-X

@article{657cabfb86a440619a37a08e22628d10,

title = "Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial",

abstract = "BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.",

keywords = "Aged, Androgen Antagonists/therapeutic use, Anilides/therapeutic use, Combined Modality Therapy, Drug Administration Schedule, Gonadotropin-Releasing Hormone/agonists, Humans, Male, Middle Aged, Nitriles/therapeutic use, Oligopeptides/administration & dosage, Prostate-Specific Antigen/blood, Prostatectomy, Prostatic Neoplasms/pathology, Tosyl Compounds/therapeutic use",

author = "Parker, {Chris C} and Howard Kynaston and Cook, {Adrian D} and Clarke, {Noel W} and Catton, {Charles N} and Cross, {William R} and Petersen, {Peter M} and Persad, {Rajendra A} and Pugh, {Cheryl A} and Fred Saad and John Logue and Heather Payne and Bower, {Lorna C} and Chris Brawley and Mary Rauchenberger and Maroie Barkati and Bottomley, {David M} and Klaus Brasso and Chung, {Hans T} and Chung, {Peter W M} and Ruth Conroy and Alison Falconer and Vicky Ford and Goh, {Chee L} and Heath, {Catherine M} and James, {Nicholas D} and Charmaine Kim-Sing and Ravi Kodavatiganti and Malone, {Shawn C} and Morris, {Stephen L} and Abdenour Nabid and Ong, {Aldrich D} and Rakesh Raman and Sree Rodda and Paula Wells and Jane Worlding and Parulekar, {Wendy R} and Parmar, {Mahesh K B} and Sydes, {Matthew R} and {RADICALS investigators}",

year = "2024",

doi = "10.1016/S0140-6736(24)00549-X",

language = "English",

volume = "403",

pages = "2416--2425",

journal = "Lancet",

issn = "0140-6736",

publisher = "The/Lancet Publishing Group",

number = "10442",

}

TY - JOUR

T1 - Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer

T2 - a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

AU - Parker, Chris C

AU - Kynaston, Howard

AU - Cook, Adrian D

AU - Clarke, Noel W

AU - Catton, Charles N

AU - Cross, William R

AU - Petersen, Peter M

AU - Persad, Rajendra A

AU - Pugh, Cheryl A

AU - Saad, Fred

AU - Logue, John

AU - Payne, Heather

AU - Bower, Lorna C

AU - Brawley, Chris

AU - Rauchenberger, Mary

AU - Barkati, Maroie

AU - Bottomley, David M

AU - Brasso, Klaus

AU - Chung, Hans T

AU - Chung, Peter W M

AU - Conroy, Ruth

AU - Falconer, Alison

AU - Ford, Vicky

AU - Goh, Chee L

AU - Heath, Catherine M

AU - James, Nicholas D

AU - Kim-Sing, Charmaine

AU - Kodavatiganti, Ravi

AU - Malone, Shawn C

AU - Morris, Stephen L

AU - Nabid, Abdenour

AU - Ong, Aldrich D

AU - Raman, Rakesh

AU - Rodda, Sree

AU - Wells, Paula

AU - Worlding, Jane

AU - Parulekar, Wendy R

AU - Parmar, Mahesh K B

AU - Sydes, Matthew R

AU - RADICALS investigators

PY - 2024

Y1 - 2024

N2 - BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

AB - BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

KW - Aged

KW - Androgen Antagonists/therapeutic use

KW - Anilides/therapeutic use

KW - Combined Modality Therapy

KW - Drug Administration Schedule

KW - Gonadotropin-Releasing Hormone/agonists

KW - Humans

KW - Male

KW - Middle Aged

KW - Nitriles/therapeutic use

KW - Oligopeptides/administration & dosage

KW - Prostate-Specific Antigen/blood

KW - Prostatectomy

KW - Prostatic Neoplasms/pathology

KW - Tosyl Compounds/therapeutic use

UR - http://www.scopus.com/inward/record.url?scp=85194427694&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(24)00549-X

DO - 10.1016/S0140-6736(24)00549-X

M3 - Journal article

C2 - 38763153

SN - 0140-6736

VL - 403

SP - 2416

EP - 2425

JO - Lancet

JF - Lancet

IS - 10442

ER -

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this