mHSPC

The Rapidly Evolving Management Strategy Of Metastatic Hormone-Sensitive Prostate Cancer

Prostate cancer (PCa) is the most common non-cutaneous malignancy in US men and the second most common cause of cancer-specific death.¹The American Cancer Society estimates that in 2019, approximately 174,650 new cases will be diagnosed, and 31,620 cancer-specific deaths will occur.²

Treatment Advances in Metastatic Hormone-Sensitive Prostate Cancer

Metastatic hormone-sensitive prostate cancer (mHSPC) is the disease space whereby men have metastatic prostate cancer and have never received (ie. are sensitive to) androgen deprivation therapy (ADT). mHSPC previously constituted ~30% of prostate cancer cases ¹, however, from 2004-2012 secondary to PSA testing, the estimate was ~5% of cases ². Many experts in the field suggest that with decreased PSA screening over the last few years, as a result of the United States Preventative Services Task Force (USPSTF) Grade D recommendation for PSA screening (subsequently upgraded to C ³), that these estimates are likely to once again increase ⁴. Typically, these patients have been treated with ADT alone, at which point the clock begins ticking towards a castration-resistant time point and eventual mortality. Since 2015, we have seen several landmark trials published that have added therapies to ADT for these men, favorably impacting overall survival (OS). This article will discuss the effect of docetaxel and abiraterone therapy among men with mHSPC and review the subsequent literature following reporting of these trials.

Docetaxel and mHSPC

In 2015, the CHAARTED trial changed the landscape of treatment of men with mHSPC. This trial randomized 790 men with mHSPC to receive either ADT + docetaxel (75 mg/m2 every 3 weeks for six cycles) (ADT-DOCE) or ADT alone, with OS as an endpoint ⁵. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT-DOCE than with ADT alone (57.6 months vs. 44.0 months; HR 0.61; 95%CI 0.47-0.80). Furthermore, the median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the ADT-DOCE group, as compared with 11.7 months in the ADT-alone group (HR 0.61, 95%CI 0.51-0.72). This trial ushered into clinical practice ADT-DOCE as the standard of care for men with mHSPC.

Following reporting of the USA led CHAARTED trial, the UK STAMPEDE trial reported their OS outcomes of ADT-DOCE vs ADT alone ⁶. STAMPEDE uses a multi-arm, multi-stage platform, recruiting men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term ADT. Patients were randomized 2:1:1:1 to standard of care (SOC; ADT alone), SOC + zoledronic acid (SOC + ZA), SOC + docetaxel (ADT-DOCE), or SOC with both zoledronic acid and docetaxel (SOC + ZA + Doc). There were 2,962 men randomized between 2005 and 2013, including 1,817 (61%) men with M+ disease, 448 (15%) with N+/X M0, and 697 (24%) men who were N0M0. Over a median follow-up of 43 months (IQR 30–60), there were 415 deaths in the control group, with a median OS of 71 months (IQR 32-not reached (NR)) for SOC, NR (IQR 32-NR) for SOC + ZA (HR 0.94, 95%CI 0.79–1.11), 81 months (41-NR) for ADT-DOCE (HR 0.78, 95%CI 0.66–0.93), and 76 months (IQR 39-NR) for SOC + ZA + Doc (HR 0.82, 95%CI 0.69–0.97). These results recapitulated the findings of CHAARTED, as well as noting that zoledronic acid did not show an OS improvement when added to ADT alone.

The GETUG-AFU15 phase III RCT was a French initiative, also testing ADT-DOCE vs ADT alone ⁷. Among 385 patients over a median follow-up of 83.9 months, the median OS was 62.1 months (95%CI 49.5–73.7) for ADT-DOCE and 48.6 months (95% CI, 40.9–60.6) for ADT alone (HR 0.88, 95%CI 0.68–1.14), thus failing to find a significant OS advantage for the addition of ADT-DOCE. The authors also analyzed several subgroups, post-hoc survival analyses, finding no ADT-DOCE advantage for men with high-volume disease (HR 0.78, 95%CI 0.56–1.09), low-volume disease (HR 1.02, 95%CI 0.67–1.55), nor for those with de novo metastatic disease (HR 0.93, 95%CI 0.69–1.25).

This year, the CHAARTED trial published an updated survival analysis: at a median follow-up 53.7 months, the HR for OS was 0.72 (95%CI 0.59-0.89) favoring docetaxel over ADT standard of care, a 28% risk reduction of death compared to 39% in the first analysis ⁸. In subset analyses, the benefit was observed across all subgroups with two notable exceptions. Specifically, patients with a low burden of disease (HR 1.04, 95%CI 0.7-1.55) or those who had prior local therapy (HR 0.97, 95%CI 0.58-1.56) did not seem to experience a benefit through the addition of docetaxel to standard ADT.

Abiraterone and mHSPC

For nearly two years, ADT-DOCE was SOC for men with mHSPC. However, in 2017, two large phase III RCTs reported outcomes combining ADT + abiraterone acetate + prednisone (ADT-ABI) in this population, adding additional therapeutic options to the clinical repertoire ^{9, 10}. LATITUDE was an international trial evaluating ADT-ABI compared to ADT alone among men with high-risk mHSPC ⁹. High-risk was defined as meeting at least two of three criteria: (i) Gleason score ≥8, (ii) presence of ≥3 lesions on bone scan, or (iii) presence of measurable visceral lesions. Patients were randomized 1:1 to either ADT-ABI (1000 mg abiraterone acetate + 5mg prednisone daily) (n=597) or ADT + placebo (n=602). The co-primary endpoints were OS and radiographic progression-free survival (rPFS). Secondary endpoints included time to pain progression, PSA progression, next symptomatic skeletal event, chemotherapy, and subsequent prostate cancer therapy. Over a median follow-up of 30.4 months, patients treated with ADT-ABI had a 38% risk reduction of death (HR 0.62, 95%CI 0.51-0.76) compared to ADT + placebo. Median OS was not yet reached in the ADT-ABI arm, compared to 34.7 months in the ADT + placebo arm. There was also a 53% risk of reduction of radiographic progression or death for patients treated with ADT-ABI compared to ADT alone (HR 0.47, 95%CI 0.39-0.55). Additionally, there was a statistically significant improvement across all secondary endpoints for ADT-ABI:

1. Time to PSA progression (HR 0.30, 95%CI 0.26-0.35)
2. Time to pain progression (HR 0.70, 95%CI 0.58-0.83)
3. Time to next symptomatic skeletal event (HR 0.70, 95%CI 0.54-0.92)
4. Time to chemotherapy (HR 0.44, 95%CI 0.35-0.56)
5. Time to subsequent prostate cancer therapy (HR 0.42, 95%CI 0.35-0.50)

Reporting at the same time as LATITUDE was the STAMPEDE abiraterone acetate arm ¹⁰. Inclusion criteria for the STAMPEDE ABI study included men with locally advanced or metastatic prostate cancer, including newly diagnosed with N1 or M1 disease, or any two of the following: stage T3/4, PSA ≥ 40 ng/mL, or Gleason score 8-10. Patients undergoing prior radical prostatectomy or RT were eligible if they had more than one of the following: PSA ≥ 4 ng/mL and PSADT < 6 months, PSA ≥ 20 ng/mL, N1, or M1 disease. These patients were then randomized 1:1 to SOC (ADT for ≥2 years, n=957) vs ADT-ABI (1000 mg abiraterone acetate + prednisone 5 mg daily, n=960). Treatment with RT was mandated in patients with N0M0 disease, while strongly encouraged for N1M0 patients. Primary outcomes were OS and failure-free survival (FFS), where failure was defined as PSA failure, local failure, lymph node failure, distant metastases or prostate cancer death. Over a median follow-up of 40 months, there was a 37% relative improvement in OS (HR 0.63, 95%CI 0.52-0.76) favoring ADT-ABI. Furthermore, ADT-ABI demonstrated a 71% improvement in FFS (HR 0.29, 95%CI 0.25-0.34) as well as significantly decreasing SREs among the entire cohort (HR 0.46, 95%CI 0.37-0.58) and specifically in the M1 cohort (HR 0.45, 95%CI 0.37-0.58).

Based on the interim analysis findings of LATITUDE, the study was unblinded at the time of the first interim analysis. At the ASCO 2018 annual meeting, Dr. Fizazi presented longer-term efficacy analyses from this phase III trial ¹¹. Median follow-up at the time of the second analysis was 41.0 months (range 0.1-54.0), 10.6 months longer than the initial analysis. There were 205 patients (34%) in the ADT-ABI arm and 70 patients (12%) in the ADT + placebo arm (of whom 57 patients (81%) had crossed over to ADT-ABI) who remained on treatment. Importantly, updated OS results continued to favor ADT-ABI compared to ADT alone (NR vs 36.7 months; HR 0.638, 95%CI 0.538-0.758). The results of the secondary endpoints also continued to favor ADT-ABI: (i) time to pain progression: 47.4 vs. 17. 9 months; HR 0.723, 95%CI 0.608-0.860; (ii) time to SRE: NR vs NR; HR 0.739, 95%CI 0.579-0.942; (iii) time to chemotherapy initiation: NR vs 47.3 months; HR 0.471, 95%CI 0.378-0.586; (iv) time to subsequent prostate cancer therapy: NR vs 21.2 months; HR 0.428, 95%CI 0.361-0.507.

Comparing Docetaxel and Abiraterone

Given the STAMPEDE design, recruitment of patients for the comparison of ADT-DOCE versus ADT alone overlapped for 16 months with recruiting patients for ADT-ABI + versus ADT alone ¹². This design allowed for a comparison of randomized patients receiving ADT-DOCE to those receiving ADT-ABI. Stratified randomization allocated patients 2:1:2 to ADT alone, or ADT-DOCE, or ADT-ABI. There were 566 patients randomized to ADT-DOCE (n=189) and ADT-ABI (n=377). At a median follow up 4 years, the OS HR was 1.16 (95%CI 0.82-1.65; insignificantly favoring ADT-DOCE), FFS HR was 0.51 (95%CI 0.39-0.67; significantly favoring ADT-ABI), PFS HR was 0.65 (95%CI 0.48-0.88; significantly favoring ADT-ABI), MFS HR was 0.77 (95%CI 0.57-1.03; insignificantly favoring ADT-ABI), and SRE survival HR was 0.83 (95%CI 0.55-1.25; insignificantly favoring ADT-ABI).

A second study used network meta-analysis methodology whereby an indirect comparison of two or more therapeutic options is possible through a common comparator arm. Wallis et al. ¹³ compared ADT-DOCE to ADT-ABI using data from GETUG, CHAARTED, LATITUDE, and the STAMPEDE trials. Overall, 6,067 patients were included: 1,181 (19.5%) patients who received ADT-DOCE, 1,557 (25.7%) patients who received ADT-ABI, and 3,329 (54.9%) patients who received ADT alone. The pooled HR for OS was 0.75 (95%CI 0.63–0.91) for ADT-DOCE versus ADT alone and 0.63 (95%CI 0.55–0.72) for ADT-ABI versus ADT alone. The indirect comparison of ADT-ABI to ADT-DOCE demonstrated no statistically significant difference in OS between treatments (HR 0.84, 95%CI 0.67– 1.06), and the findings were similar among patients with metastatic disease. Despite the lack of statistical significance, Surface Under the Cumulative Ranking Analysis (SUCRA) reported an 89% probability that ADT-ABI was the preferred first-line treatment option. Taken together, these studies suggest that although there is a trend favoring ADT-ABI for several outcomes, as the data currently stands, both ADT-ABI and ADT-DOCE are acceptable options for men with mHSPC.

Patient Reported Outcomes

Given that both ADT-ABI and ADT-DOCE improve OS outcomes, it becomes important to assess the impact on quality of life (QoL) metrics. A recently published analysis of the LATITUDE data assessing patient reported outcomes showed that patients receiving ADT-ABI had improved outcomes ¹⁴. The median time to worst pain intensity progression assessed by the BPI-SF score was not reached in either the ADT-ABI group (NR, 95%CI NR-NR; 25th percentile 11.1 months, 95%CI 9.22-18.4) or ADT group (NR, 95%CI NR-NR; 25th percentile 5.6 months, 95%CI 4.63-7.39), however with an HR of 0.63 (95%CI 0.52-0.77) favoring ADT-ABI. Similar findings were reported for median time to worst fatigue intensity (HR 0.65, 95%CI 0.53-0.81). Finally, the median time to deterioration of functional status assessed by the FACT-P total score scale was 12.9 months (95%CI 9.0-16.6) in the ADT-ABI group versus 8.3 months (7.4-11.1) in the ADT alone group (HR 0.85, 95%CI 0.74-0.99).

Similarly, QoL data from the CHAARTED trial has also recently been published ¹⁵. Among the 790 men randomized, 90% completed FACT-P at baseline, 86% at 3 months, 83% at 6 months, 78% at 9 months, and 77% at 12 months. ADT-DOCE patients reported a statistically significant decline in FACT-P at 3 months (p < 0.001) but FACT-P did not differ significantly between baseline and 12 months (p = 0.38). ADT-DOCE FACT-P scores were significantly lower at 3 months (p = .02) but significantly higher at 12 months (p = .04) when compared with ADT alone FACT-P scores. Furthermore, ADT-DOCE patients reported significantly lower Functional Assessment of Chronic Illness Therapy-Fatigue scores at 3 months than ADT alone patients (p < .001).

At this year’s GU ASCO meeting, Feyerabend et al. ¹⁶ presented results of an indirect treatment comparison of ADT-ABI and ADT-DOCE on patient-reported outcomes among men with mHSPC. The mean change from baseline was based on differences in FACT-P and BPI scores between active vs control arms in LATITUDE ⁹ (intention-to-treat ITT population) and CHAARTED ⁵. The probability of ADT-ABI being superior to ADT-DOCE at 3, 6, 9, and 12 months after treatment was based on fixed-effects Bayesian network meta-analysis. The authors found that the benefit in patient-reported outcomes with ADT-ABI vs ADT-DOCE was seen at 3 months and sustained for at least 1 year after treatment. This was consistent at each time point and for both FACT-P and BPI tools. The Bayesian probability of ADT-ABI being the better treatment for patient-reported outcomes ranged from 92.3% to 100%, with higher probabilities noted earlier in follow-up.

Future Directions

Cost Effectiveness

There are significant cost differences when considering docetaxel or abiraterone. For example, for 100 patients with mHSPC, six cycles of upfront docetaxel (including visits, infusion, and cost of the drug) would cost $10,000 per patient. By subsequently adding abiraterone for an eventual rising PSA associated with CRPC ($8,000/month USD; with a median time to progression to CRPC of 18 months), this would cost $144,000 per patient ($15 million to treat 100 patients) with upfront docetaxel. For upfront abiraterone, at a median time to progression of 36 months (at $8,000/month USD) + $10,000 for post-abiraterone docetaxel, the total cost would be $30 million to treat 100 patients. Experts have suggested that there are several additional reasons to use docetaxel prior to abiraterone: (i) completed in 18 weeks with short term adverse events; (ii) docetaxel utilized earlier in the disease process allows chemotherapy treatment before the patient becomes too frail.

Dr. Nicholas James and colleagues recently reported results of their analysis from STAMPEDE assessing whether adding docetaxel to the standard of care represents a cost-effective use of healthcare resources in M0 and M1 prostate cancer patients ¹⁷. Health outcomes and costs in the UK NHS were modeled using EuroQol (EQ-5D) and resource use data collected within the STAMPEDE trial. Lifetime predictions of costs, changes in predicted survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Compared to patients allocated standard of care, docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients. Docetaxel was estimated to extend discounted QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients. QALY gains in M0 patients were driven by the beneficial effect of delayed and reduced relapse – ie. patients receiving docetaxel spend more time in the hormone-sensitive state without treatment failure and less time with CRPC. Docetaxel was cost-effective both in M1 patients (ICER = £5,514/QALY vs. standard of care) and M0 patients (higher QALYs, lower costs vs. standard of care). The authors concluded that the probabilistic sensitivity analysis indicated a very high probability (> 99%) that docetaxel is cost-effective in both M0 and M1 patients.

Subsequent Therapy

Since CHAARTED was published nearly four years ago, data regarding subsequent therapy among patients initially receiving ABI-DOCE during the mHSPC disease state are emerging. Among 136 patients treated with upfront ABI-DOCE included in a multi-institutional study, the median time to CRPC was 19.6 months (IQR 16.6-22.6) ¹⁸. Sixty patients (44%) received ≥1 treatment for CRPC, including 48 patients (80%) receiving a second-generation hormonal therapy. Among these patients, 22 received abiraterone acetate, 20 enzalutamide, and six a novel CYP-17 inhibitor on trial (ASN-001). Patients receiving a second-generation hormonal therapy as the first treatment for mCRPC had a median radiographic PFS of 9.0 months (95%CI 6.9-11.2) compared with 3.0 months (95%CI, 1.5-4.5) for patients who received a non-second-generation hormonal therapy (p = 0.024).

A separate multi-institutional study assessed the efficacy of abiraterone acetate vs enzalutamide in the mCRPC setting stratified by utilization of ADT-DOCE vs ADT alone in the mHSPC setting ¹⁹. Among 102 patients with mCRPC, 50 (49%) had previously received ADT alone, while 52 (51%) had ADT-DOCE. No statistically significant difference in any of the evaluated outcomes was observed between the two cohorts, however, deaths in the ADT-DOCE group were 12 compared to 21 in the ADT alone, after a median follow-up of 24.4 and 29.8 months, respectively.

Ongoing Trials

One of the most anticipated trials currently ongoing is the PEACE-1 phase III trial (NCT01957436) assessing SOC (ADT +/- docetaxel) vs SOC + abiraterone + prednisone vs SOC + local radiotherapy vs SOC + local radiotherapy + abiraterone + prednisone for men with de novo M1 prostate cancer. The co-primary outcomes are overall and progression-free survival. This trial has a target accrual of 1,168 patients, with more than 80% of patients already recruited. This trial will ultimately test whether ADT + abiraterone + docetaxel is even better than ADT-ABI or ADT-DOCE.

Conclusions

Results of several large phase III RCTs over the past four years have improved survival and quality of life outcomes among men with mHSPC. Both docetaxel and abiraterone acetate in combination with ADT is the standard of care for patients in this disease state. Results of clinical trials assessing additional combinatorial therapy (ie. PEACE-1) are eagerly anticipated as we continue to strive for improved survival among prostate cancer patients with aggressive hormone-sensitive disease.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD, MSc

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6. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, 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;387:1163-77.
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8. Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, 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;36:1080-7.
9. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377:352-60.
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11. Fizazi K, Feyerabend S, Matsubara N, Ozguroglu M, Fein L, Rodriguez-Antolin A, et al. Longer term preplanned efficacy and safety analysis of abiraterone acetate + prednisone (AA + P) in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC) from the phase 3 LATITUDE trial. J Clin Oncol. 2018;36:Abstr 5023.
12. Sydes MR, Spears MR, Mason MD, Clarke NW, Dearnaley DP, de Bono JS, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol. 2018;29:1235-48.
13. Wallis CJD, Klaassen Z, Bhindi B, Goldberg H, Chandrasekar T, Farrell AM, 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;73:834-44.
14. Chi KN, Protheroe A, Rodriguez-Antolin A, Facchini G, Suttman H, Matsubara N, et al. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018;19:194-206.
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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 disease^{12, 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 cancer^{9, 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.

mHSPC

Docetaxel and mHSPC

Abiraterone and mHSPC

Comparing Docetaxel and Abiraterone

Patient Reported Outcomes

Future Directions

Conclusions

Agents with proven survival benefit - Docetaxel

Agents with proven survival benefit – Abiraterone Acetate

Agents with proven survival benefit – Enzalutamide

Agents with proven survival benefit – Apalutamide

Agents with proven survival benefit – Comparative data

Agents without proven survival benefit

Conclusions

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