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.
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.
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.
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.
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.