The Evolving Landscape of Evidence-based Treatment in Metastatic Hormone Sensitive Prostate Cancer

Agents with proven survival benefit - Docetaxel

Docetaxel was the first agent to demonstrate a survival benefit in men with metastatic hormone sensitive prostate cancer (mHSPC)7-10. However, not all trials assessing the use of docetaxel in this disease space have demonstrated a survival benefit. As reported by Gravis and colleagues, the GETUF-AFU 15 trial enrolled men with 385 men with metastatic prostate cancer and randomized them to androgen deprivation therapy (whether by bilateral orchiectomy or luteinizing hormone released hormone agonists alone or in combination with non-steroidal anti-androgens) alone (n=193) or in combination with up to nine cycle of docetaxel (n=192)7. Patients were required to have a Karnofsky score >70 and were excluded if previous chemotherapy for metastatic prostate cancer had been received or if ADT had been administered within 12 months of randomization. Notably, median PSA at the time of randomization was 26 ng/mL in the control arm and 27 ng/mL in the experimental arm which are much lower than those of patients in other trials. Correspondingly, there was a higher proportion of patients with low volume metastatic disease. Over a median follow-up of 82.9 months, the authors demonstrated no survival benefit to the addition of docetaxel to ADT (hazard ratio (HR) 0.9, 95% confidence interval (CI) 0.7 to 1.2).

Shortly after the publication of GETUG-AFU 15, the CHAARTED trial was published8. The overall methodology was very similar to GETUG-AFU 15, with 393 men randomized to medical or surgical castration alone and 397 men randomized to ADT plus up to six cycles of docetaxel. Less than two years of adjuvant ADT was allowed as long as at least 12 months had passed between the end of adjuvant ADT administration and trial enrollment. As alluded to above, patients in the CHAARTED trial had more aggressive disease, as a higher proportion of patients had Gleason 8-10 histology and high-volume metastases, and the cohorts had a much higher median PSA level (52 ng/mL in the control arm and 51 ng/mL in the experimental arm). As reported by Sweeney and colleagues, the CHAARTED trial demonstrated a significant survival advantage to the early administration of docetaxel in men with metastatic hormone-sensitive prostate cancer (HR 0.61, 95% CI 0.47 to 0.80).

Settling the impasse was one of the first read-outs from the multiplatform STAMPEDE trial. Unlike GETUG-AFU 15 and CHAARTED which included only men with metastatic hormone-sensitive prostate cancer, STAMPEDE also included men with node-positive disease (15% of study cohort) and high-risk N0, M0 disease (24% of study cohort). As reported by James et al.9, this publication assessed the factorial effect of docetaxel, zoledronic acid, and both in addition to ADT. In keeping with the results of CHAARTED, James et al. reported a significant survival benefit to the addition of docetaxel in men with metastatic hormone-sensitive disease (HR 0.76, 95% CI 0.63 to 0.91).

Subsequent subgroup analyses from the CHAARTED cohort have demonstrated that the survival benefit associated with early administration of docetaxel may be restricted to men with high volume metastases11. This finding may also help to reconcile the observed differences between GETUG-AFU 15 and CHAARTED/STAMPEDE.

Agents with proven survival benefit – Abiraterone Acetate

The next major advance was the demonstration that abiraterone acetate improved survival when administered in men with metastatic hormone-sensitive disease12, 13. Published concurrently, the LATITUDE trial and STAMPEDE trial both demonstrated a significant survival advantage in men receiving abiraterone compared to placebo in combination with ADT.

The LATITUDE trial enrolled particularly high-risk men: all men had metastatic prostate cancer with at least two additional high-risk features (Gleason score 8-10, at least three bony metastases, and visceral metastases). Previously treated men, whether with chemotherapy, radiation therapy, or surgery were excluded except for if this was administered with palliative intent. Patients were randomized to ADT alone (n=602) or in combination with abiraterone acetate (1000 mg daily) plus prednisone (5 mg daily) (n=597). Over a median follow-up of 30.4 months, the authors reported a significant survival advantage among patients receiving abiraterone acetate (HR 0.62, 95% CI 0.51 to 0.76).

As with their prior publication, this report of the STAMPEDE trial included men with metastatic, node-positive, and high-risk N0, M0 disease. James et al. report an almost identical survival benefit (HR 0.63, 95% CI 0.52 to 0.76) as the LATITUDE investigators.

Agents with proven survival benefit – Enzalutamide

Two trials have recently reported assessing the role of enzalutamide in men with metastatic hormone-sensitive prostate cancer.

In the ARCHES trial presented at the ASCO GU Cancers symposium in 2019, 1150 men with metastatic hormone-sensitive prostate cancer were randomized to ADT with or without enzalutamide. To date, the overall survival data are immature but radiographic progression-free survival was significantly improved (HR 0.39, 95% CI 0.30 to 0.50)14.

Shortly after at the annual ASCO meeting in June 2019, the ENZAMET trial was reported and concurrently published15. Unlike the aforementioned studies, this trial included an active control: patients were randomized to enzalutamide or standard, first-generation non-steroidal anti-androgen (bicalutamide, nilutamide, or flutamide). Additionally, the use of docetaxel was allowed in addition to the prescribed enzalutamide. The trial accrued 1125 patients and approximately 45% of patients were planned to receive docetaxel. Enzalutamide given within 12 weeks of initiating ADT was associated with a significant survival benefit (HR 0.67, 95% CI 0.52 to 0.86).

Agents with proven survival benefit – Apalutamide

Finally, in July 2019, the TITAN trial was published assessing apalutamide in metastatic hormone-sensitive prostate cancer16. The study schema closely resembled previously mentioned trials: 525 patients were accrued and randomized to apalutamide or placebo, in addition to ADT. Approximately 10% had previously received docetaxel and nearly 2/3 had high-volume disease. As may be expected, administration of apalutamide was associated with improved overall survival (HR 0.67, 95% CI 0.50 to 0.89). Notably, apalutamide was well tolerated with only marginally higher adverse event rates than placebo.

Agents with proven survival benefit – Comparative data

As docetaxel and abiraterone acetate were the first two agents to demonstrate survival advantage, and subsequently be approved, for men with metastatic hormone-sensitive prostate cancer, these agents have subsequently been compared using both network meta-analysis and non-randomized within-trial comparisons from the STAMPEDE cohort. Wallis et al. published the first comparative data in this disease space17 demonstrating no significant difference in overall survival between patients receiving abiraterone acetate as compared to docetaxel, in addition to ADT (HR 0.84, 95% CI 0.67 to 1.06). However, Bayesian analysis suggested a high probability that abiraterone may be the preferred agent (surface under the cumulative ranking analysis: 89% probability). Subsequent network meta-analyses and a non-randomized comparison from the STAMPEDE cohort have demonstrated similar results with the latter suggesting a greater benefit to abiraterone in outcomes that are more dependent on the androgen axis (eg. PSA-response) than those which are not (eg. overall survival).

To our knowledge, there are no published direct randomized comparisons of these agents, though, undoubtedly, network meta-analyses including enzalutamide and apalutamide will shortly be forthcoming.

Agents without proven survival benefit

In addition to the aforementioned docetaxel, abiraterone acetate, apalutamide, and enzalutamide, a number of other agents have been examined in this space. Based on a rationale that skeletal-related events may significantly affect the disease trajectory, and survival, of patients with metastatic prostate cancer, a number of groups have examined the effect of bone-targeted agents such as bisphosphonates in this disease space. In 2003, Dearnaley and colleagues published the results of the MRC PR05 trial which examined the use of oral sodium clodronate in patients with metastatic prostate cancer18. This trial demonstrated a non-significant improvement in biochemical progression-free survival (HR 0.80, 95% CI 0.62 to 1.03).

Between 2004 and 2017, three additional trials were published assessing the use of zoledronic acid in men with metastatic hormone-sensitive prostate cancer9, 19, 20: Smith et al. reported on the results of the CALGB 90202 trial, James et al. utilized the STAMPEDE trial platform9, and Kamba and colleagues reported the phase III ZAPCA trial assessing combined androgen blockade with or without the addition of zoledronic acid. In each case, the authors did not find a benefit to the early administration of zoledronic acid in men with metastatic hormone-sensitive prostate cancer.

In addition to bone targeting agents, Mason and colleagues utilized the STAMPEDE platform to assess whether the addition of celecoxib, either on its own or with zoledronic acid, would improve survival for men with advanced hormone-sensitive prostate cancer but found no benefit21.

Conclusions

Treatment options in patients with metastatic hormone-sensitive prostate cancer have dramatically changed in the past five years. Randomized data have demonstrated a significant survival benefit to docetaxel, abiraterone acetate, apalutamide, and enzalutamide in this disease space. However, direct comparative data are lacking and treatment choice is thus informed by indirect comparisons utilizing network meta-analysis as well as individual physician and patient preference.

Published Date: November 19th, 2019

Written by: Zachary Klaassen, MD, MSc, and Christopher J.D. Wallis, MD, Ph.D
References: 1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65(2):87-108.
2. Weiner AB, Matulewicz RS, Eggener SE, et al. Increasing incidence of metastatic prostate cancer in the United States (2004-2013). Prostate Cancer Prostatic Dis 2016; 19(4):395-397.
3. Kitagawa Y, Namiki M. Prostate-specific antigen-based population screening for prostate cancer: current status in Japan and future perspective in Asia. Asian J Androl 2015; 17(3):475-80.
4. Huggins C SR, Hodges CV. Studies on prostate cancer: II. The effects of castration on advanced carcinoma of the prostate gland., Vol. 43. Archives of Surgery, 1941. pp. 209-223.
5. Hellerstedt BA, Pienta KJ. The current state of hormonal therapy for prostate cancer. CA Cancer J Clin 2002; 52(3):154-79.
6. Wu JN, Fish KM, Evans CP, et al. No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period. Cancer 2014; 120(6):818-23.
7. Gravis G, Boher JM, Joly F, et al. Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol 2016; 70(2):256-62.
8. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015; 373(8):737-46.
9. 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, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387(10024):1163-77.
10. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use [03-03-2015]. Journal [serial online].
11. 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 CHAARTED Trial. J Clin Oncol 2018; 36(11):1080-1087.
12. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 2017; 377(4):338-351.
13. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377(4):352-360.
14. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2019:JCO1900799.
15. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019; 381(2):121-131.
16. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2019; 381(1):13-24.
17. Wallis CJD, Klaassen Z, Bhindi B, et al. Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naive Prostate Cancer: A Systematic Review and Network Meta-analysis. Eur Urol 2018; 73(6):834-844.
18. Dearnaley DP, Sydes MR, Mason MD, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003; 95(17):1300-11.
19. Kamba T, Kamoto T, Maruo S, et al. A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial. Int J Clin Oncol 2017; 22(1):166-173.
20. Smith MR, Halabi S, Ryan CJ, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol 2014; 32(11):1143-50.
21. Mason MD, Clarke NW, James ND, et al. Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naive Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial. J Clin Oncol 2017; 35(14):1530-1541.