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Zoledronic Acid in First-Line Treatment of Prostate Cancer
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Zoledronic Acid in First-Line Treatment of Prostate Cancer By Michael Pinkawa, MD, PhD, Associate Editor Received Jun 14, 2016. Accepted for publication Jun 22, 2016
In this issue’s Oncology Scan (1-2), we review new possibilities for systemic therapy combined with radiation in locally advanced prostate cancer. Androgen suppression (AS) has been an established first-line systemic treatment of advanced prostate cancer for many decades. The addition of radiation therapy is known to improve overall survival in comparison with AS alone in locally advanced prostate cancer without the evidence of metastases (3-5). Several new systemic treatments, such as docetaxel, cabazitaxel, enzalutamide, arbiraterone, radium-223, and sipuleucel-T, have been introduced in recent years in castrate-refractory prostate cancer, on the basis of studies showing a survival benefit (6). Zoledronic acid (ZA) and denosumab are bonetargeted agents, reducing the risk of skeletal-related events (7, 8). Following the evidence in the palliative situation, the potential benefit as first-line treatment needs to be defined. Bisphosphonates have been shown to be effective in prostate cancer cell lines in vitro, demonstrating apoptosis induction, inhibition of cell growth, invasive behavior, and angiogenic factors (9). They have the potential to enhance antitumor activity of known cytotoxic drugs. The addition of zoledronic acid to AS could thus decrease the incidence of bone metastases and prevent AS-induced osteopenia and fractures. Recently published randomized studies tried to define the role of ZA in firstline treatment of locally advanced prostate cancer (6, 10, 11). Denham et al. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): An open-labeled, randomised, phase 3 factorial trial. Lancet Oncol 2014. (10) Summary: The first aim of the study was to compare 18 months of AS (intermediate-term AS, ITAS) with Int J Radiation Oncol Biol Phys, Vol. 97, No. 1, pp. 6e8, 2017 0360-3016/$ - see front matter http://dx.doi.org/10.1016/j.ijrobp.2016.06.2453
6 months of AS (short-term AS, STAS) in combination with external beam radiation therapy with or without brachytherapy boost. Second, ZA was added to ITAS and STAS, resulting in a 2 2 factorial trial. Between the years 2003 and 2007, 1071 patients with T2a tumors, prostate-specific antigen (PSA) level 10 ng/ mL, and Gleason score 7 or T2b-4 tumors regardless of PSA level and Gleason score were included. All patients were treated with 6 months of neoadjuvant AS (22.5 mg leuprorelin every 3 months), followed by 12 months of AS in the ITAS groups. Zoledronic acid was given in a dose of 4 mg for 18 months every 3 months. The primary endpoint was prostate cancerespecific mortality. After a median follow-up of 7.4 years, prostate cancere specific mortality or all-cause mortality did not differ between control and experimental groups. The use of ZA prevented osteopenia, and an additional 12 months of AS did not increase vertrebral fractures (12). Compared with STAS, STAS plus ZA increased the risk of bone progression (hazard ratio [HR 1.9], 95% confidence interval [CI] 1.14-3.17; PZ.012), but ITAS plus ZA reduced PSA progression (HR 0.71, 95% CI 0.53-0.95; PZ.021) and the risk of secondary therapeutic interventions (HR 0.67, 95% CI 0.48-0.95; PZ.024). Post hoc analyses suggested that the reductions of PSA progression and the need for secondary therapeutic interventions were restricted to tumors with a Gleason score 8 to 10, whereas ITAS was superior to STAS in Gleason score <8 cancers. Long-term morbidity and quality-of-life scores were not affected. Comments: With only a short follow-up for the analysis of bone metastases or survival, this study supports the benefit of longer AS for locally advanced and high-risk prostate cancer treated with external beam radiation therapy with or without brachytherapy boost. Short-term AS plus 18 months of ZA is not a useful treatment option for these
Volume 97 Number 1 2017
patients (increasing bone progression). The addition of ZA to ITAS reduces PSA progression, particularly in Gleason score 8 to 10 patients. Zoledronic acid does not add a benefit for patients with lower Gleason scores. A synergistic effect of AS and ZA can be postulated. Bisphophonates should not be given without AS. Although benefits of combined AS and ZA were found, further follow-up is needed before introducing ZA in the first-line treatment. External validation is needed to support the interaction of Gleason score with ZA.
Denham et al. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial. Radiother Oncol 2015. (11) Summary: Radiation dose escalation (RDE) and AS are both used to treat patients with locally advanced prostate cancer, on the basis of results of randomized trials. The relative effects are unknown, so that less AS might be needed in dose-escalated definitive radiation therapy treatments. Stratification ensured that radiation dose and technique were balanced across trial arms. The main endpoint of this subanalysis was a composite of clinically diagnosed local progression or PSA progression with a PSA doubling time 6 months. Fine and Gray competing risk modeling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Composite local progression declined coherently in the 66-, 70-, and 74-Gy (all in 2-Gy fractions) external beam radiation therapy groups and was lowest in the high-dose-rate (HDR) brachytherapy boost group (46 Gy external beam radiation therapy and 19.5 Gy HDR in 3 fractions over 24 hours)d incidences were 22%, 15%, 13%, and 7%, respectively (HDR vs 70 Gy: HR 0.43, 95% CI 0.33-0.56; P<.001). Urethral strictures increased, with crude incidences of 0.8%, 0.9%, 3.8%, and 12.7%, respectively. Compared with STAS, ITAS also significantly reduced local progression (HR 0.59, 95% CI 0.49-0.72; P<.001). An interaction of ZA or Gleason score was not found for this endpoint. The addition of ZA reduced the risk of urethral strictures only in the STAS group. No significant effect of ZA was found on local prostatic progression or urethral strictures in combination with ITAS. Radiation dose escalation and increasing duration of AS independently reduced local prostatic progression and increased the rate of urethral strictures. Comments: This analysis demonstrated independent effects of RDE and duration of AS, although magnetic resonance imaging was not available in all participating centers, and thus only local progression surrogates have been used. Zoledronic acid neither changed local progression nor affected urethral stricture rates, if combined with ITAS.
Oncology Scan
7
The results suggest that AS has an established role in locally advanced or high-risk prostate cancer even in doseescalated treatments. However, a higher toxicity riskdurethral strictures were specifically evaluated in this reportdneeds to be balanced against possible benefits. A recently published randomized trial confirms the survival benefit of long-term AS (24 months) in comparison with STAS (4 months), with high-dose radiation therapy (total dose range 76-82 Gy) (13).
James et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016. (6) Summary: The study recruited men with high-risk, locally advanced, metastatic or recurrent prostate cancer (at least 2 of T3/T4, Gleason score 8-10, and PSA 40 ng/mL) who have started first-line long-term hormone therapy for at least 2 years. Patients were fit for chemotherapy, with no clinically significant cardiovascular history. Stratified randomization allocated patients 2:1:1:1 to standard of care (SOC) only, SOC plus ZA (4 mg, 6 3-weekly cycles, then 4-weekly until 2 years), SOC plus docetaxel (Doc; 75 mg/ m2 6 3-weekly cycles) or SOC with ZA and Doc. A total of 2962 patients were randomized between 2005 and 2013: 61% with M1 disease, 15% with N1M0 disease, and 24% with N0M0 disease. Radiation therapy was encouraged for men with N0M0 disease to 2011, then mandated. The primary outcome measure was overall survival. Compared with SOC only, median overall survival was significantly longer for SOC þ Doc (HR 0.78, 95% CI 0.66-0.93; PZ.006) and for SOC þ ZA þ Doc (HR 0.82, 95% CI 0.69-0.97; PZ.022). In SOC, SOC þ ZA, SOC þ Doc, and SOC þ ZA þ Doc, respective 5-year survival rates of 39%, 43%, 50%, and 46% were determined, but with grade 3 or higher toxicity during the first 6 months of 17%, 15%, 36%, and 39%, respectively. In men with nonmetastatic disease, recurrence-free survival was improved with Doc. ZA showed no benefit on failure-free or overall survival. Time to first skeletal-related event was improved with SOC þ Doc and SOC þ ZA þ Doc, but not with SOC þ ZA. Comments: This study supports the early application of docetaxel with long-term hormone therapy in this high-risk, mostly metastatic patient population. The majority of patients were 60 to 70 years old (interquartile range) and without comorbidities. Taking into account a higher risk of serious treatment-related toxicity, this concept should be considered for high-risk patients with a good performance status. No clinical advantage of the addition of first-line ZA could be shown. The findings of this study are supported by a
8
Oncology Scan
systematic review and meta-analysis, evaluating the addition of docetaxel and bisphosphonates to standard of care (14). Summarizing the available data on ZA in first-line treatment, a relevant beneficial effect does not exist for a patient requiring predominantly a systemic treatment. The advantage of a combination of radiation therapy and intermediate- or long-term hormonal therapy with ZA needs to be further explored with longer follow-up and additional studies.
International Journal of Radiation Oncology Biology Physics
7.
8.
9. 10.
References 1. Buyyounouski MKK. Oncology scandnew treatment and no treatment: Enduring issues in the management of prostate cancer. Int J Radiat Oncol Biol Phys 2015;91:1-2. 2. Song D. Oncology Scandrising stars, fading stars, and shooting stars: New trends in prostate cancer management. Int J Radiat Oncol Biol Phys 2014;89:4-6. 3. Mottet N, Peneau M, Mazeron JJ, et al. Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: An open randomised phase 3 trial. Eur Urol 2012;62:213-219. 4. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: A randomised, phase 3 trial. Lancet 2011;378:2104-2111. 5. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG7/SFUO-3): An open randomised phase III trial. Lancet 2009;373: 301-308. 6. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive,
11.
12.
13.
14.
multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163-1177. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879-882. Smith MR, Egerdie B, Hernandez TN, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361:745-755. Neville-Webbe HL, Holen I, Coleman RE. The anti-tumour activity of bisphosphonates. Cancer Treat Rev 2002;28:305-319. Denham JW, Joseph D, Lamb DS, et al. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): An open-label, randomised, phase 3 factorial trial. Lancet Oncol 2014;15: 1076-1089. Denham JW, Steigler A, Joseph D, et al. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial. Radiother Oncol 2015;115:301-307. Denham JW, Nowitz M, Joseph D, et al. Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer. BJU Int 2014; 114:344-353. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): A randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:320-327. Vale CL, Burdett S, Rydzewska LH, 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 metaanalyses of aggregate data. Lancet Oncol 2016;17:243-256.
Radiation Oncology biology
physics
www.redjournal.org
Zoledronic Acid in First-Line Treatment of Prostate Cancer By Michael Pinkawa, MD, PhD, Associate Editor Received Jun 14, 2016. Accepted for publication Jun 22, 2016
In this issue’s Oncology Scan (1-2), we review new possibilities for systemic therapy combined with radiation in locally advanced prostate cancer. Androgen suppression (AS) has been an established first-line systemic treatment of advanced prostate cancer for many decades. The addition of radiation therapy is known to improve overall survival in comparison with AS alone in locally advanced prostate cancer without the evidence of metastases (3-5). Several new systemic treatments, such as docetaxel, cabazitaxel, enzalutamide, arbiraterone, radium-223, and sipuleucel-T, have been introduced in recent years in castrate-refractory prostate cancer, on the basis of studies showing a survival benefit (6). Zoledronic acid (ZA) and denosumab are bonetargeted agents, reducing the risk of skeletal-related events (7, 8). Following the evidence in the palliative situation, the potential benefit as first-line treatment needs to be defined. Bisphosphonates have been shown to be effective in prostate cancer cell lines in vitro, demonstrating apoptosis induction, inhibition of cell growth, invasive behavior, and angiogenic factors (9). They have the potential to enhance antitumor activity of known cytotoxic drugs. The addition of zoledronic acid to AS could thus decrease the incidence of bone metastases and prevent AS-induced osteopenia and fractures. Recently published randomized studies tried to define the role of ZA in firstline treatment of locally advanced prostate cancer (6, 10, 11). Denham et al. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): An open-labeled, randomised, phase 3 factorial trial. Lancet Oncol 2014. (10) Summary: The first aim of the study was to compare 18 months of AS (intermediate-term AS, ITAS) with Int J Radiation Oncol Biol Phys, Vol. 97, No. 1, pp. 6e8, 2017 0360-3016/$ - see front matter http://dx.doi.org/10.1016/j.ijrobp.2016.06.2453
6 months of AS (short-term AS, STAS) in combination with external beam radiation therapy with or without brachytherapy boost. Second, ZA was added to ITAS and STAS, resulting in a 2 2 factorial trial. Between the years 2003 and 2007, 1071 patients with T2a tumors, prostate-specific antigen (PSA) level 10 ng/ mL, and Gleason score 7 or T2b-4 tumors regardless of PSA level and Gleason score were included. All patients were treated with 6 months of neoadjuvant AS (22.5 mg leuprorelin every 3 months), followed by 12 months of AS in the ITAS groups. Zoledronic acid was given in a dose of 4 mg for 18 months every 3 months. The primary endpoint was prostate cancerespecific mortality. After a median follow-up of 7.4 years, prostate cancere specific mortality or all-cause mortality did not differ between control and experimental groups. The use of ZA prevented osteopenia, and an additional 12 months of AS did not increase vertrebral fractures (12). Compared with STAS, STAS plus ZA increased the risk of bone progression (hazard ratio [HR 1.9], 95% confidence interval [CI] 1.14-3.17; PZ.012), but ITAS plus ZA reduced PSA progression (HR 0.71, 95% CI 0.53-0.95; PZ.021) and the risk of secondary therapeutic interventions (HR 0.67, 95% CI 0.48-0.95; PZ.024). Post hoc analyses suggested that the reductions of PSA progression and the need for secondary therapeutic interventions were restricted to tumors with a Gleason score 8 to 10, whereas ITAS was superior to STAS in Gleason score <8 cancers. Long-term morbidity and quality-of-life scores were not affected. Comments: With only a short follow-up for the analysis of bone metastases or survival, this study supports the benefit of longer AS for locally advanced and high-risk prostate cancer treated with external beam radiation therapy with or without brachytherapy boost. Short-term AS plus 18 months of ZA is not a useful treatment option for these
Volume 97 Number 1 2017
patients (increasing bone progression). The addition of ZA to ITAS reduces PSA progression, particularly in Gleason score 8 to 10 patients. Zoledronic acid does not add a benefit for patients with lower Gleason scores. A synergistic effect of AS and ZA can be postulated. Bisphophonates should not be given without AS. Although benefits of combined AS and ZA were found, further follow-up is needed before introducing ZA in the first-line treatment. External validation is needed to support the interaction of Gleason score with ZA.
Denham et al. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial. Radiother Oncol 2015. (11) Summary: Radiation dose escalation (RDE) and AS are both used to treat patients with locally advanced prostate cancer, on the basis of results of randomized trials. The relative effects are unknown, so that less AS might be needed in dose-escalated definitive radiation therapy treatments. Stratification ensured that radiation dose and technique were balanced across trial arms. The main endpoint of this subanalysis was a composite of clinically diagnosed local progression or PSA progression with a PSA doubling time 6 months. Fine and Gray competing risk modeling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Composite local progression declined coherently in the 66-, 70-, and 74-Gy (all in 2-Gy fractions) external beam radiation therapy groups and was lowest in the high-dose-rate (HDR) brachytherapy boost group (46 Gy external beam radiation therapy and 19.5 Gy HDR in 3 fractions over 24 hours)d incidences were 22%, 15%, 13%, and 7%, respectively (HDR vs 70 Gy: HR 0.43, 95% CI 0.33-0.56; P<.001). Urethral strictures increased, with crude incidences of 0.8%, 0.9%, 3.8%, and 12.7%, respectively. Compared with STAS, ITAS also significantly reduced local progression (HR 0.59, 95% CI 0.49-0.72; P<.001). An interaction of ZA or Gleason score was not found for this endpoint. The addition of ZA reduced the risk of urethral strictures only in the STAS group. No significant effect of ZA was found on local prostatic progression or urethral strictures in combination with ITAS. Radiation dose escalation and increasing duration of AS independently reduced local prostatic progression and increased the rate of urethral strictures. Comments: This analysis demonstrated independent effects of RDE and duration of AS, although magnetic resonance imaging was not available in all participating centers, and thus only local progression surrogates have been used. Zoledronic acid neither changed local progression nor affected urethral stricture rates, if combined with ITAS.
Oncology Scan
7
The results suggest that AS has an established role in locally advanced or high-risk prostate cancer even in doseescalated treatments. However, a higher toxicity riskdurethral strictures were specifically evaluated in this reportdneeds to be balanced against possible benefits. A recently published randomized trial confirms the survival benefit of long-term AS (24 months) in comparison with STAS (4 months), with high-dose radiation therapy (total dose range 76-82 Gy) (13).
James et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016. (6) Summary: The study recruited men with high-risk, locally advanced, metastatic or recurrent prostate cancer (at least 2 of T3/T4, Gleason score 8-10, and PSA 40 ng/mL) who have started first-line long-term hormone therapy for at least 2 years. Patients were fit for chemotherapy, with no clinically significant cardiovascular history. Stratified randomization allocated patients 2:1:1:1 to standard of care (SOC) only, SOC plus ZA (4 mg, 6 3-weekly cycles, then 4-weekly until 2 years), SOC plus docetaxel (Doc; 75 mg/ m2 6 3-weekly cycles) or SOC with ZA and Doc. A total of 2962 patients were randomized between 2005 and 2013: 61% with M1 disease, 15% with N1M0 disease, and 24% with N0M0 disease. Radiation therapy was encouraged for men with N0M0 disease to 2011, then mandated. The primary outcome measure was overall survival. Compared with SOC only, median overall survival was significantly longer for SOC þ Doc (HR 0.78, 95% CI 0.66-0.93; PZ.006) and for SOC þ ZA þ Doc (HR 0.82, 95% CI 0.69-0.97; PZ.022). In SOC, SOC þ ZA, SOC þ Doc, and SOC þ ZA þ Doc, respective 5-year survival rates of 39%, 43%, 50%, and 46% were determined, but with grade 3 or higher toxicity during the first 6 months of 17%, 15%, 36%, and 39%, respectively. In men with nonmetastatic disease, recurrence-free survival was improved with Doc. ZA showed no benefit on failure-free or overall survival. Time to first skeletal-related event was improved with SOC þ Doc and SOC þ ZA þ Doc, but not with SOC þ ZA. Comments: This study supports the early application of docetaxel with long-term hormone therapy in this high-risk, mostly metastatic patient population. The majority of patients were 60 to 70 years old (interquartile range) and without comorbidities. Taking into account a higher risk of serious treatment-related toxicity, this concept should be considered for high-risk patients with a good performance status. No clinical advantage of the addition of first-line ZA could be shown. The findings of this study are supported by a
8
Oncology Scan
systematic review and meta-analysis, evaluating the addition of docetaxel and bisphosphonates to standard of care (14). Summarizing the available data on ZA in first-line treatment, a relevant beneficial effect does not exist for a patient requiring predominantly a systemic treatment. The advantage of a combination of radiation therapy and intermediate- or long-term hormonal therapy with ZA needs to be further explored with longer follow-up and additional studies.
International Journal of Radiation Oncology Biology Physics
7.
8.
9. 10.
References 1. Buyyounouski MKK. Oncology scandnew treatment and no treatment: Enduring issues in the management of prostate cancer. Int J Radiat Oncol Biol Phys 2015;91:1-2. 2. Song D. Oncology Scandrising stars, fading stars, and shooting stars: New trends in prostate cancer management. Int J Radiat Oncol Biol Phys 2014;89:4-6. 3. Mottet N, Peneau M, Mazeron JJ, et al. Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: An open randomised phase 3 trial. Eur Urol 2012;62:213-219. 4. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: A randomised, phase 3 trial. Lancet 2011;378:2104-2111. 5. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG7/SFUO-3): An open randomised phase III trial. Lancet 2009;373: 301-308. 6. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive,
11.
12.
13.
14.
multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163-1177. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879-882. Smith MR, Egerdie B, Hernandez TN, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361:745-755. Neville-Webbe HL, Holen I, Coleman RE. The anti-tumour activity of bisphosphonates. Cancer Treat Rev 2002;28:305-319. Denham JW, Joseph D, Lamb DS, et al. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): An open-label, randomised, phase 3 factorial trial. Lancet Oncol 2014;15: 1076-1089. Denham JW, Steigler A, Joseph D, et al. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial. Radiother Oncol 2015;115:301-307. Denham JW, Nowitz M, Joseph D, et al. Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer. BJU Int 2014; 114:344-353. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): A randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:320-327. Vale CL, Burdett S, Rydzewska LH, 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 metaanalyses of aggregate data. Lancet Oncol 2016;17:243-256.