Castration-naive metastatic prostate cancer: reshaping old paradigms

KEYWORDS:

• Abiraterone acetate
• castration-naive prostate cancer
• docetaxel
• LATITUDE trial
• STAMPEDE trial

Androgen deprivation therapy (ADT) has been the mainstay of metastatic prostate cancer treatment since the 1940s. In the last few years, the addition of docetaxel to standard ADT has revolutionized the outcome of metastatic castration-naive prostate cancer patients. Three randomized phase III trials have investigated the role of up-front chemotherapy in newly diagnosed metastatic prostate cancer patients.

The CHAARTED study [1], a randomized phase III trial, enrolled 790 patients with metastatic, hormone-sensitive prostate cancer who were randomized to receive either ADT alone (human luteinizing hormone-releasing hormone - LHRH agonist/antagonist therapy or surgical castration) or ADT plus docetaxel. In both groups, 72.8% of patients had received no prior local therapy for prostate cancer with curative (rather than palliative) intent; however, study population was heterogeneous, due to the presence of patients who had metastases at diagnosis and cases who had received a previous locoregional treatment.

Median follow-up on 23 April 2016 was 53.7 months: the median overall survival (mOS) was 57.6 months for ADT plus docetaxel (95% confidence interval [CI]: 52.0–63.9) and 47.2 months for ADT alone (95% CI: 41.8–52.8) (hazard ratio [HR]: 0.73; p = 0.0018) [2]. One of the most important features of this trial was stratification according to disease burden (high- vs. low-volume disease), showing that the clinical benefit of docetaxel with ADT is limited to patients with a high-volume disease (defined as the presence of visceral metastases and/or four or more bone metastases with at least one outside of the vertebral column and pelvis) in comparison to low-volume disease (HR: 0.63 vs. 1.04; p < 0.0001 vs. 0.86, respectively).

In the STAMPEDE trial [3], a five-stage, multi-arm, multistage, adaptive controlled trial, patients were randomized to standard of care (SOC) only, SOC plus zoledronic acid (ZA), and SOC plus docetaxel or SOC plus ZA and docetaxel. Ninety-eight percent of patients in all groups received an LHRH-based ADT as SOC.

All patients enrolled were hormone sensitive, but the study population was quite heterogeneous; 61% of patients had a newly diagnosed metastatic disease, 15% had node-positive disease, and 24% had a nonmetastatic disease (N0/M0). Moreover, 6% of patients were previously treated with local therapy. mOS was 71 months for SOC only, not reached for SOC plus ZA (HR: 0.94; 95% CI: 0.79–1.11; p = 0.450), 81 months for SOC plus docetaxel (HR: 0.78; 95% CI: 0.66–0.93; p = 0.006), and 76 months for SOC plus ZA and docetaxel (HR: 0.82; CI: 0.69–0.97; p = 0.022).

On the other hand, the GETUG-15 trial enrolled 385 patients that were randomized to receive ADT plus docetaxel or ADT alone. The study showed no statistically significant difference in the primary end point of OS between the two treatment groups with an mOS of 58.9 months in the ADT plus docetaxel versus 54.2 months in the ADT-alone arm (HR: 1.01; 95% CI: 0.75–1.36). The conclusion of this trial was that docetaxel should not be used as a first-line treatment for patients with castration-naive metastatic prostate cancer [4]. However, differences in the study population and sample size among these three studies may justify different conclusions.

The results of these trials have been analyzed in a meta-analysis, which has provided substantial and reliable evidence that the addition of docetaxel to SOC improves survival of patients with metastatic castration-sensitive disease, with an absolute improvement of around 9% at 4 years [5]. For men with nonmetastatic disease, the analysis has underlined an 8% reduction in absolute failure rates at 4 years with docetaxel, but there is insufficient evidence to assess the effects on survival. Considering all these results, the use of docetaxel for six cycles in castration-naive patients is now introduced in everyday clinical practice.

At the 2017 American Society of Clinical Oncology Annual Meeting, two randomized phase III trials have been presented: the LATITUDE study [6] and the STAMPEDE study [7], both of which evaluate the efficacy of early abiraterone acetate (AA) in castration-naive patients.

AA has provided a survival benefit in metastatic castration-resistant prostate cancer (mCRPC) patients, in both pre- and post-docetaxel settings [8,9], but considering pathogenesis and the androgen-driven nature of prostate cancer, it has been hypothesized, and recently demonstrated, that AA should play a role also in a very early phase of disease.

The LATITUDE trial is a randomized, placebo-controlled, phase III trial which has enrolled patients with a high-risk, metastatic, castration-naive prostate cancer diagnosed no more than 3 months from randomization. These patients had at least two of three high-risk prognostic factors including a Gleason score of 8 or more, three or more bone metastases, or at least one visceral metastasis. Patients were randomized to receive AA plus prednisone (5 mg/daily) plus ADT (LHRH agonists at the investigator’s discretion) or surgical castration vs. ADT/surgical castration plus placebo. At the first interim analysis, after a median follow-up of 30.4 months, AA showed an overall survival rate at 3 years of 66% vs. 49% in the placebo group, with a reduction of the risk of death of 38% in the AA arm (HR: 0.62; p < 0.001). AA provided a longer median radiographic progression-free survival (rPFS) than placebo (33 vs. 14.8 months, HR: 0.47), with a risk reduction of rPFS or death of 53%. All the secondary and exploratory end points favored the AA arm, which was also characterized by a good safety profile, in keeping line with data from mCRPC. In particular, Grade 3 or 4 adverse events (AEs) were reported in 63% of patients treated with AA and in 48% of those in the placebo arm. AEs leading to a treatment discontinuation were 12% in the AA group and 10% in the placebo group. In this study, a higher incidence of mineralocorticoid-related hypertension and hypokalemia was observed in patients treated with AA. The apparent increase in these AEs could be related to a lower dose of prednisone used in this trial than that used in previous studies of AA, but also to a longer duration of treatment. Hypertension and hypokalemia were both medically manageable and rarely required treatment discontinuation. These results strongly encourage the use of AA in addition to standard ADT in men with newly diagnosed, metastatic, castration-naive prostate cancer with high-risk features.

The addition of AA to ADT in newly diagnosed castration-naive prostate cancer has been evaluated also in one arm of the STAMPEDE trial. Patients included in this trial differed from those of LATITUDE study since 52% of patients had a metastatic disease, 20% had node-positive disease, and 28% had nonmetastatic disease. STAMPEDE trial has also demonstrated a survival advantage in the combination arm of AA and ADT (bilateral orchidectomy, LHRH analogs, and LHRH antagonists): 3-year survival was 83% for AA plus ADT and 76% for ADT alone. The 3-year failure-free survival was 75% in the AA plus ADT arm and 45% in the ADT-alone arm. The 3-year PFS was 80% in the combination arm and 62% for ADT-alone arm. The advantage of AA in this setting was observed in all subgroups analyzed. The prevalence of Grade 3 or higher AEs was 47% in the combination group and 33% in the group of patients treated with ADT alone. The most important AEs observed were hypertension, mild increases in aminotransferase levels, and respiratory disorders, which were acceptable and in line with previous studies with AA in castration-resistant prostate cancer.

In the light of the results of these two trials, the emerging role of AA in this setting is becoming evident, but several issues need to be addressed:

1. For the first time in this setting, patient population in the LATITUDE trial is homogeneous (98% of patients had a high Gleason score and more than three bone metastases at screening and 97% of patients had bone metastases as site of disease) and balanced between the two treatment arms. This is very important for the interpretation of the trial results, but it also represents an information for optimal patients’ selection.

2. AA and docetaxel will become two treatment options for metastatic castration-naive prostate cancer. However, these two agents have different safety profiles, and the choice should be tailored on patients’ characteristics. AA has a better tolerability profile than docetaxel, and it is more manageable than chemotherapy. In LATITUDE and STAMPEDE trials, AA was associated with a higher incidence of mineralocorticoid-related AEs than the previous studies in mCRPC, in particular hypertension and hypokalemia, but these events were overall manageable. Moreover, in both studies, incidence of any grade AEs was similar between the two arms, and even AEs leading to treatment discontinuation or death did not differ significantly between AA and placebo groups. The lack of a clear difference in terms of toxicity profile between the two groups suggests us that AEs may not be necessarily related to AA.

3. In the LATITUDE and STAMPEDE trials, median age of patients receiving AA was higher (68 and 67 years, respectively) than in CHAARTED trial (median age 64 years), and many patients had an Eastern Cooperative Oncology Group (ECOG) performance status (≥1). These characteristics can help us to choose the best treatment: AA should be a valid option also in patients with less favorable performance status and in older patients, who usually are not the ideal candidate to receive up-front docetaxel.

4. AA has showed a great efficacy in newly diagnosed high-risk prostate cancer patients; this let us suppose that the same efficacy could be observed also in real-life unselected patients treated outside clinical trials.

5. Up-front AA treatment in castration-naive prostate cancer patients has significantly improved survival. This would modify our approach to this disease, reshaping the therapeutic scenario. Furthermore, there is a growing interest toward the mechanisms of resistance to AA (e.g. expression of truncated androgen receptor variants in circulating tumor cells) [10]: a better understanding of these mechanisms could drive treatment choice.

6. Considering the results of the two trials, also pharmacoeconomics should be considered. Chemotherapy is administered up to six cycles every 3 weeks followed by standard ADT, while treatment with AA could have a significant longer duration (in the LATITUDE trial, the median time that the patients received AA was 24 months, while in the STAMPEDE trial, it was 23.7 months) and subsequently significant higher costs. To this regard even if AA has a more manageable profile and could become a treatment option for a wider number of patients, we should take into consideration also the impact of both long-term exposure to ADT plus AA as well as the treatment costs. However, clinical benefit and good safety profile might justify higher costs.

Considering all the above aspects, AA plus ADT will represent a valid option for men with a newly diagnosed metastatic, high-risk, castration-naive prostate cancer. These findings illustrate the very topical issue of discussing and weighing treatment options with the patient in order to tailor treatment.

Declaration of interest

G Procopio has received fees from Bayer, Janssen and Astellas for serving on the advisory boards of these companies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not received any funding.