Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-risk Prostate Cancer—Results from the Prospective, Randomised, Open-label Phase III SPCG-13 Trial

1 This is the accepted manuscript of the article, which has been published in European Urology. 2019, 76(6), 823-830. https://doi.org/10.1016/j.eururo.2019.08.010 Title page Docetaxel versus surveillance after radical radiotherapy for intermediate-or high-risk prostate cancer - results from the prospective randomized, open-label phase III SPCG 13 trial. Kellokumpu-Lehtinen P-L1, Hjälm-Eriksson M2, Thellenberg-Karlsson C3, Åström L4, Franzen L5, Fransson A-S6, Leskinen M7, Zeke M8, Huttunen T9, Ginman C10 on behalf of the Investigators of the Scandinavian Prostate Cancer Study no 13 1Tampere University Hospital, Tampere, Finland, 2 Department of Surgery Capio ST: Görans hospital and Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden, 3 Department of Radiation Sciences, Oncology, Umeå University Hospital, Umeå, Sweden, 4Uppsala University Hospital, Uppsala, Sweden, 5Sundsvall University Hospital, Sundsvall, Sweden, 6Gävle Central Hospital, Gävle, Sweden, 7Seinäjoki Central Hospital, Seinäjoki, Finland, 8Växjö Central Hospital, Växjö, Sweden, 94Pharma, Turku, Finland, 10 Karlstad Central Hospital, Karlstad, Sweden Send proofs and correspondence to: Pirkko-Liisa Kellokumpu-Lehtinen, M.D., PhD, Professor Professor of Radiotherapy and Oncology Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital P.O. Box 2000 33521 Tampere Finland Telephone; +358 50 5951103 Fax; +358 3 31163009 e-mail; [email protected] 2 Key words; Prostate cancer, adjuvant, docetaxel, randomized trial, radical radiotherapy. Word count of text; 2799 Word count of the abstract; 395 3 Take Home Message In a randomized setting, intermediateor high-risk prostate cancer patients treated with adjuvant chemotherapy with docetaxel following radical radiotherapy and ADT did not show improved biochemical disease-free survival compared to those who underwent radical radiotherapy and ADT alone. More adverse events occurred with the combined treatment, but there were less PSA relapses than were estimated to occur in both groups. 4 Background: Docetaxel combined with androgen deprivation therapy (ADT) has improved patient survival for advanced prostate cancer (PCa). Objective: This randomized trial evaluated if six courses of docetaxel improved the biochemical disease-free survival (BDFS) after radical radiotherapy (RT) for intermediateor high-risk PCa patients. Design, setting and participants: A total of 376 patients were randomized in this multinational phase III study and received either 6 cycles of adjuvant docetaxel 75 mg/m2 every 3 weeks without continuous prednisone (Arm A, n=188) or surveillance (Arm B, n=188) after RT (NTC006653848). Neoadjuvant/adjuvant ADT was mandatory for all the patients. The primary endpoint was a rising PSA > 2 ng/ml above the nadir PSA value. Intermediateor high-risk prostate cancer was defined as T2 with a Gleason score (GS) of 4+3, PSA>10; T2, GS 8-10 any PSA; or any T3. The patients were followed for 5 years by assessing PSA levels every 3 months for two years and every 6 months thereafter. Outcome measurements and statistical analysis: The study power was 89% to detect a difference between groups in biochemical disease-free survival (BDFS), and the sample size calculation accounted for the T2/T3 distribution, where a 12%/15% difference in BDFS was assumed for the T2/T3 patients. Results and limitations: All six cycles were completed in 147 (78%) of the patients in arm A. The median age was 67 years in both treatment groups, and 75% had T3 disease, and 46% had GS 8-10. The median follow-up was 59 months (range 1 to 111 months). The primary endpoint was observed for 58 patients in Arm A (docetaxel) and for 57 patients in Arm B (surveillance). The Kaplan-Meier analysis showed no difference in the BDFS curves (p=0.6) between the 5 treatment groups. The 5-year estimated biochemical progression rates were 31% for Arm A and 28% for Arm B. Febrile neutropenia occurred in 16% of the docetaxel patients. No deaths were related to the docetaxel treatment. There were 43 deaths during the trial, including 20 in Arm A and 23 in Arm B, of which 9 and 7, respectively, were due to PCa. The Hazard Ratio from Cox multivariate analysis for PSA progression of Arm A (docetaxel) vs Arm B (surveillance) was 1.14 (95% CI 0.79 to 1.64, p=0.5). Conclusions: Adjuvant docetaxel without prednisone did not improve BDFS after radical radiotherapy with ADT for intermediateor high-risk prostate cancer. Patient summary: We compared six cycles of adjuvant docetaxel given after radical external radiotherapy plus ADT to surveillance in intermediateand high-risk localized prostate cancer. We found no overall benefit in this setting. 6 Introduction Radical prostatectomy or radiotherapy is evidence based treatment options for intermediateor high-risk localized prostate cancer (PCa) (1,2). However, the risk of biochemical recurrence after surgery or radiotherapy for high-risk disease is approximately 50% at 5 years (3-5). After a recurrence with distant metastases, several new treatment options are available today, including enzalutamide, abiraterone, cabazitaxel, sipuleucil-T, enzalutamide, abiraterone, and radium-223 (6,7). However, metastatic disease eventually leads to death. Higher stage, higher Gleason score (GS) and high prostate specific antigen (PSA) levels correlate to cancer specific and overall survival in long-term follow-ups (5). In 2004, two randomized trials showed that a docetaxel-based treatment given every third week prolonged survival in metastatic castrate resistant prostate cancer (mCRPC), and later, a biweekly dosing of docetaxel was shown to be better tolerated and gave a survival gain in our study (8-10). In addition, two large prospective randomized trials (CHAARTED and STAMPEDE) have shown survival gain with docetaxel in metastatic hormone naïve prostate cancer combined to androgen deprivation therapy (11-13). In early breast cancer, adjuvant docetaxel-based regimen was accepted as standard of care over ten years ago (14, 15). However, today using gene profiling, like in the TAILORx trial with hormone receptor positive and Her2 negative breast cancer patients, we could avoid adjuvant chemotherapy in many breast cancer patients (16). The SPCG-group initiated two prospective open labelled, randomized trials to evaluate a possible benefit of docetaxel as an adjuvant treatment after local curative treatment in prostate cancer e.g., SPCG-12 and SPCG-13. In the SPCG-12 trial, the patients were randomized to receive six cycles of docetaxel without ADT or surveillance after radical prostatectomy. However, docetaxel was not beneficial in our SPCG-12 trial, as recently published by Ahlgren and co-workers (17) 7 The aim of this SPCG-13 trial was to evaluate if docetaxel combined with neo/adjuvant hormonal therapy improved biochemical disease-free survival (BDFS) after a radical radiotherapy for highor intermediate-risk PCa patients. 8 Patients and methods The key inclusion criteria in the SPCG trial-13 were the following: men > 18 and ≤75 years of age; WHO/ECOG performance status 0 – 1; histologically proven adenocarcinoma of the prostate within 12 months prior to randomization; one of the following: T2 with Gleason 7 (4+3) and PSA >10 ng/ml to < 70 ng/ml or T2 with Gleason 8-10; PSA < 70 ng/ml or any T3 tumours. According to the NCCN guidelines SPCG-13 patients belong to intermediateor highrisk group (5). Prior neoadjuvant hormone therapy was mandatory for all the patients, and adequate haematological, liver and kidney function (less than 1.5 x UNL for creatinine, less than 1.5 X UNL for liver laboratory values except bilirubin < UNL) was required. The key exclusion criteria were metastatic disease, pathologically or clinically node positive cancer, a history of previous malignant disease (exceptions were made for basal cell carcinoma and squamous cell carcinoma of the skin and curatively treated malignant disease, which had been disease free for the past five years), previous radiotherapy to pelvic region, previous chemotherapy within five years, systemic corticosteroids within 6 months prior to randomization, unstable cardiovascular disease within 6 months prior to randomization or active untreated infectious disease known allergy to Polysorbate 80, other serious illness or medical condition, symptomatic peripheral neuropathy > CTCAE grade 2 and unable to cooperate.. All the patients gave written informed consent. The ethics committee approved the trial. The trial identifier was NTC006653848 (www.clinicaltrial.gov). The primary endpoint of the trial was PSA progression. The secondary endpoints were PSA doubling time, Quality of Life (QoL, measured by FACT-P, 18), safety (using Common Terminology Criteria for Adverse Events (CTCAE) version 3∙0 (http://ctep.cancer.gov), metastases free survival, and overall survival. 9 Between May 2007 and August 2012, a total of 378 patients satisfying the inclusion and exclusion criteria were randomized after completing RT between the control or six courses of docetaxel. ADT was continued according the protocol. Permuted block randomization within each stratum was used. Stratification factors were centre and T stage (T2 vs T3). Randomization request was recorded on a clinical case report form . It was sent to separate randomization unit by fax to 4Pharma. Thus, the site personnel did not had access to the randomization list. Most patients (N=320, 85%) were enrolled from Sweden. The defined endpoint was PSA relapse, according to the ASTRO-RTOG guidelines (19), with progression of PSA defined >2.0 ng/ml above nadir, with censoring at the last PSA measurement, and discontinuations during PSA follow-up (including deaths from other causes) censored at the time of death/discontinuation. PSA measurements were done every three months after finishing RT for two years then every 6 months until PSA progression or end of trial. Docetaxel 75 mg/m2 i.v. in 60 minutes was given on day one of each 21-day cycle and started within three months after radiotherapy (Arm A). Premedication with corticosteroids was used. No continuous prednisone was prescribed during the docetaxel therapy. Arm B; No docetaxel treatment. Neoadjuvant LH-RH analogue 3 months before RT, during RT and 3 months after RT (altogether, there were 3 injections every third month or monthly injections, treatment lasted 9 months). Both groups received 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) alone or combined to brachytherapy, tumour dose at least 74 Gray. Statistical calculations The null hypothesis of ‘no difference in the PSA recurrences experience between the treatment groups’ was tested against the corresponding nondirectional alternative hypothesis using the log-rank test. Since the recurrence times were assumed to follow mixing distributions, the 16 for publication. The funder of the study (Sanofi) had no impact on study design, data collection, data analysis, data interpretation or writing of the report. The representatives from the company were regularly updated on how the study was proceeding and participated in the investigators meetings. Acknowledgements:To all the investigators, study coordinators and nurses within the SPCG13 participating centers, including the University Hospitals, Karolinska University Hospital, Uppsala University Hospital, Örebro University Hospital, Hospitals, Karlstad, Sundsvall, Eskilstuna, Växjö and Jönköping in Sweden and the University Hospital in Tampere, Hospitals in Lahti and Seinäjoki in Finland. All the patients, their families and to Sanofi for a generous research grant. This study was partly supported by the Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital. Conflicts of interest Marie Hjälm-Eriksson is a member of advisory board; Bayer and Sanofi. Camilla Thellenberg-Karlsson is a member of advisory board; Sanofi, Bayer. Speakers fee Janssen, Astellas 17 References 1. Sandra MG, Cadeddu JA, Kirby E, et al. Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part I: Risk stratification, shared decision making, and care options. J Urol 2018;199:683-690. 2. Motter N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Par 1: screening, diagnosis and local treatment with curative intent. Eur Urol 2017;71:618-29. 3. Briganti A, Karnes RJ, Gandaglia G, et al. Natural history of surgically treated high-risk prostate cancer; Urol Oncol: Seminars and Original Investigations 2015;33:163.e7-13. 4 Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017;71:618–629 5. National Comprehensive Cancer Network guidelines. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (accessed 07, November 2018). 6. Gillessen S, Attard G, Beer TM, et al. Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol. 2018;73:178-211. 7. Fitzpatrick JM, Bellmunt J, Fizazi, et al. Optimal management of metastatic castrationresistant prostate cancer: Highlights from a European expert consensus panel. Eur J Cancer 2014;50:1617-1627. 8.Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20. 18 9.Tannock IF, de Wit R, Berry WR, et al for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12 10. Kellokumpu-Lehtinen P-L, Harmenberg U, Joensuu T, et al. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol 2013;14:117-124. 11. Sweeney CJ, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2018;373;737-46. 12. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line hormonal therapy (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163-77. 13. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTEED trial. J Clin Oncol 2018;11;1080-87. 14 Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809-20. 15. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302-13. 16. Sparano JA, Gray RJ, Makover DF et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 2018;379;111-121. 17. Ahlgren G, Flodgren P, Tammela T, et al. Docetaxel versus surveillance after radical prostatectomy for high risk prostate cancer: results from the prospective randomized, openlabel phase 3 Scandinavian prostate cancer group 12 trial. Eur Urol 2018;73:870-876. 19 18. Esper P, Mo F, Chodak G, et al. Measuring quality of life in men with prostate cancer using the Functional Assessment of Cancer Therapy–prostate instrument. Urol 1997;50:9208. 19. Roach M 3rd, Hanks G, Thames H Jr, et al. biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer. Recommendations of RTOG-ASTRO Phoenix Consensus Conference. In J Rad Oncol Biol Phys 2006;65:965-74. 20. Kellokumpu-Lehtinen PL, Hjälm-Eriksson M, Thellenberg-Karlsson C, et al.. Toxicity in patients receiving adjuvant docetaxel + hormonal treatment after radical radiotherapy for intermediate or high-risk prostate cancer: a preplanned safety report of the SPCG-13 trial. Prostate Cancer Prostatic Dis 2012;15:303-307. 21.Rosenthal SA, Hu C, Sartor O, et al. Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: The randomized phase III NRG Oncology RTOG 0521 trial. J Clin Oncol 2019;March 12, https://doi.or/10.1200.18.02158. 22. Nabid A, Carrier N, Martin AG, et al. Duration of androgen deprivation therapy in highrisk prostate cancer: A randomized phase III trial. Eur Urol 2018;74:432-441. 23. Rosenthal SA, Hunt D, Sartor AO, et al. A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: Final results of radiation therapy oncology group phase 3 randomized trial NRG Oncology RTOG 9902. Int J Radiat Oncol Biol Phys 2015;93:294-302. 24. Fizazi K, Faivre L, Lesaunier F, et al. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol 2015;16:787–94. 20 25. Fizazi K, Carmel A, Florence J, et al. Updated results of GETUG-12, a phase 3 trial of docetaxel-based chemotherapy in high-risk localized prostate cancer, with a 12-year follow up. ESMO 2018. 26.Tosco L, Briganti A, D’amico AV, et al. Systematic review of systemic therapies and therapeutic combinations with local treatment for high risk localized prostate cancer. Eur Urol 2019;75:44-60. 27. Vale C L, Burdett S, Rydzewsk L H M et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol 2016;17:243–56. 28. Schweizer MT, Huang P, Kattan MW et al. Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate cancer after radical prostatectomy (TAX-3501). Cancer 2013;119:3610–18. 29. Montgomery B, Lin DW. Adjuvant chemotherapy for prostate cancer: The long and winding road. Eur Urol 2018;73:877-78. 21 Table 1. Baseline characteristics in Arm A and Arm B. Factor Adjuvant Docetaxel (Arm A, n=188) Surveillance (Arm B, n=188) Age median (IQR) 67 (63-70) 67 (63-71) PSA median before RT (ng/ml, IQR) 14.6 (8.2-29.0) 14.0 (7.0-26.0) PSA median after RT (ng/ml, IQR) 0.50 (0.15-2.80) 0.57 (0.12-1.75) T-stage T2 / T3 (%) 26 / 74 24 / 76 Gleason ≤7 / 8/9-10 (%) 56 / 26 /18 51 / 25 / 24 WHO status 0 / 1 (%) 93 / 7 95 / 5 22 Table 2. Reported number of serious adverse events (SAE) in Arm A and Arm B. Some patients several SAE´s. Type of SAE Arm A (docetaxel) N=188 Arm B (surveillance) N=188 Total Febrile neutropenia 43 0 43 Infection no neutropenia 12 2 14 Toxic/allergic reaction 2 0 2 Prostate cancer (death) 6 3 9 Other cancer 9 5 14 Other surgery 7 17 24 Cardiovascular disease 16 8 24 Chest pain (observation) 4 1 5 Thromboembolism 5 1 6 Benign bowel disease 5 1 6 Gastric ulcer 2 0 2 Other 5 3 8 Total 116 41 157 23 Table 3. Docetaxel treatment delivered at each cycle No. cycles Frequency Percent (%) Cumulative Percent (%) 0 8 4 4 112 6 11 2 6 3 14 3 5 3 16 4 5 3 19 5 5 3 23 6 147 78 100 Total 188 100 24 Table 4. Uniand multivariate Cox analysis of Hazard Ratio to have progression to end-point PSA≥2.0 ng/ml for prognostic factors and treatment Arm. Prognostic factor Univariate analysis n=375 p-value HR (95% Ci) Multivariate analysis n=375 p-value HR (95% Ci) T-stage T2 vs. T3 1.0 0.99 (0.65-1.53) 0.18 0.73 (0.46-1.15) Gleason sum (linear effect of 1 unit*) <0.001 1.47 (1.22-1.78) 0.001 1.52 (1.22-1.88) Arm A vs. Arm B 0.6 1.09 (0.76-1.58) 0.5 1.14 (0.79-1.64) 25 Table 5. Summary of adjuvant trials in prostate cancer using docetaxel combined to ADT and radical radiotherapy. CT=chemotherapy, D=docetaxel, E=Estramustine, Eto=etoposide, P= paclitaxel, RFS= recurrence free survival, OS= overall survival, BDFS= biochemical disease-free survival Trial T PSA (ng/ m l ) GS ADT CT Results GETUG-12 T 1-2 23% T 3-4 67% N+ 29% >20, 59% GS > 8, 42% 36 months DE x 4 12 yr. RFS 49% vs 36% p=0.01 RTOG 9902 T 1-2 66% T 3-4 34% 23 median GS > 8, 68% 28 months E+Eto+P x 4 10 yr. OS 65% vs 63%, P=0.8 RTOG 0521 T 1-2 73% T 3-4 27% 15 median GS 8-10, 84% 28 months D x 6 4 yr. OS 86% vs 81%, p=0.03 SPCG-13 T 2 25% T 3 75% 14 median GS 8-10, 46% 9 months D x 6 5 yr. BDFS 69% vs 70%, p=0.6