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Applying New Evidence to Optimize Care in Advanced Prostate Cancer

Matthew R. Smith, MD, PhD
Released: October 8, 2020

Metastatic Hormone-Sensitive Prostate Cancer

Patient Case With High-Volume mHSPC

Let’s begin by considering a patient case.

Case Discussion

Let’s see how our faculty panel would manage this patent with de novo metastatic hormone-sensitive prostate cancer (mHSPC) and high-volume, symptomatic disease. In our tool, 3 of our 5 faculty experts would recommend ADT plus docetaxel, 1 suggests ADT plus abiraterone, and 1 would offer ADT plus enzalutamide.

Patient Case With Diabetes

Let’s revisit another patient with mHSPC that was described in our first Presurvey question. This patient with poorly controlled diabetes was diagnosed with de novo, low-volume, symptomatic mHSPC. He is expected to live 5 years or more. When we enter this patient’s characteristics into our tool, all 5 experts recommend ADT plus enzalutamide. Two of the panel noted that apalutamide would be equally acceptable and one commented that ADT plus docetaxel would also be an option for this patient.

Now let’s take a moment to review the evidence supporting the choices of our panel of experts.

Reported RCTs in mHSPC: High-Volume/High-Risk Disease

There is abundant level one evidence that the addition of a second agent to standard ADT improves clinical outcomes in patients with mHSPC, particularly those patients with high-volume or high-risk metastatic disease, like the case of our 63-year-old patient. This has been shown in a compelling manner for docetaxel as well as androgen receptor (AR) pathway inhibitors, including abiraterone, enzalutamide, and apalutamide.[1] There is remarkable consistency of findings in this disease setting, as marked improvements in PFS as well as OS have been shown with either docetaxel or AR pathway inhibitors added to ADT. It is on the basis of these findings that ADT alone should no longer be considered the standard of care in a patient with mHSPC.

CHAARTED: Efficacy of Docetaxel Plus ADT vs ADT Alone

The CHAARTED phase III trial evaluated ADT plus docetaxel vs ADT alone in mHSPC with no previous docetaxel.[2] It was a positive study showing a significant improvement in OS with the addition of docetaxel to ADT (median: 57.6 vs 47.2 months). The HR was 0.72 (95% CI: 0.59-0.89), with a statistically significant P value (.0018).[3] The study also found that docetaxel plus ADT improved survival for patients with high-volume disease but not for those with low-volume disease. Similar results of a survival benefit for high-volume disease were seen in a post hoc analysis of the GETUG-AFU15 trial of ADT plus docetaxel vs ADT alone.[4] Conversely, the STAMPEDE trial found no difference in survival outcomes with docetaxel between low- and high-volume disease (interaction P = .827).[5]

Meta-Analysis of RCTs of Docetaxel in mHSPC

A meta-analysis of the CHAARTED, GETUG-15, and STAMPEDE randomized trials of docetaxel in mHSPC showed a 9% absolute improvement in survival at 4 years.[6]

LATITUDE: Efficacy of Abiraterone Acetate Plus ADT vs Placebo Plus ADT for mHSPC

The LATITUDE study evaluated the efficacy and safety of abiraterone plus ADT vs placebo plus ADT in patients with high-risk mHSPC.[7] This was also a positive trial, with significant improvements in both radiographic PFS (rPFS) and OS.

STAMPEDE: Trial Schema

Long-term follow-up in the STAMPEDE trial demonstrated an improvement in OS with abiraterone acetate plus prednisone over ADT alone, with median survival of 6.6 years vs 3.8 years, respectively.[8] The benefit was seen regardless of tumor volume.

To date, there has been no formal head-to-head comparison of abiraterone vs docetaxel in mHSPC, although the multicohort STAMPEDE trial allows us to do an indirect comparison between these 2 agents.[9]

STAMPEDE: Docetaxel vs Abiraterone Comparison

In STAMPEDE, there was no difference in OS between abiraterone and docetaxel, although other clinical outcomes suggest a benefit of abiraterone, including time to symptomatic skeletal events, metastatic PFS, PFS, and failure-free survival.[9]

ENZAMET: OS (Primary Endpoint)

Other AR-targeted therapies have also been evaluated in mHSPC. The phase III ENZAMET trial evaluated enzalutamide plus ADT vs a nonsteroidal antiandrogen plus ADT in this disease setting. The primary endpoint was OS.[10] ENZAMET was a positive trial, with a significant improvement in OS in patients receiving enzalutamide (HR: 0.67; 95% CI: 0.52-0.86; P = .002). There was no significant difference in benefit based on tumor volume.

ARCHES: Efficacy of Enzalutamide Plus ADT vs Placebo Plus ADT in mHSPC

The phase III ARCHES trial was the registration study for enzalutamide in mHSPC. Patients were randomized to either enzalutamide or placebo plus ADT.[11] The primary endpoint was rPFS. In ARCHES, there was a highly significant improvement in rPFS in favor of enzalutamide, with a HR of 0.39 (P < .001). The benefit was seen regardless of tumor burden. At the time of primary efficacy analysis, OS data were immature and longer follow-up is required.

TITAN: Efficacy of Apalutamide Plus ADT vs Placebo Plus ADT in mHSPC

Apalutamide has also shown benefits and is approved in mHSPC based on results from the TITAN trial. TITAN was a phase III study enrolling patients with mHSPC, who were assigned to ADT plus apalutamide or ADT plus placebo. The primary endpoints were OS and rPFS.[12]

In TITAN, apalutamide was significantly superior to placebo for rPFS, with a 52% reduction in the risk of rPFS (HR: 0.48; P < .001).[12] The 24-month rPFS rate was 68% and 48%, respectively. A subgroup analysis showed apalutamide was favored for both low- and high-volume disease.

TITAN: OS Interim Analysis

OS was also significantly improved with apalutamide, with an HR of 0.67 and a P value of .005.[12] The similarity among the results of AR-targeted therapies in mHSPC was remarkable, with almost identical HRs for OS among studies that reported that outcome.

How I Manage mHSPC

In our practice, we routinely offer intensification of systemic treatment for patients with high-risk or high-volume mHSPC. Based on tolerability and patients’ acceptance of additional treatment, we typically use abiraterone, apalutamide, or enzalutamide. Docetaxel is certainly also a reasonable choice, although in our experience, we find that patients’ acceptance of chemotherapy tends to be less than that of oral hormonal agents. For patients with diabetes, the steroids routinely administered with docetaxel may be a concern.

The AR-signaling inhibitors appear to have similar efficacy, but there is room for individualized selection of therapy based on the specific health characteristics of your patient. For instance, enzalutamide is not a good choice for patients with seizure disorders, or with behaviors that make them prone to seizure disorders, like alcoholics or binge drinkers, or those with neurologic disorders. Abiraterone is not a good choice for patients who have congestive heart failure, because it causes fluid retention or diminished ejection fraction. Abiraterone is also not the best choice for patients with difficult-to-control diabetes, because of the requirement for concurrent administration of prednisone. But for probably 80% of patients, the addition of any of the AR-signaling therapies in this setting would be appropriate.

Now let’s revisit the polling question regarding one of our earlier patient cases.

ARASENS Phase III Trial: Darolutamide in mHSPC

One of the open questions raised by these data is whether we should combine docetaxel with a novel hormonal agent in patients with mHSPC. That question will be formally addressed by the phase III ARASENS study, which is a randomized double-blind international trial involving > 300 sites in 23 countries. A total of 1300 patients with newly diagnosed mHSPC will be randomly assigned to either ADT plus docetaxel and darolutamide or ADT plus docetaxel and placebo. ARASENS is really the first study that will formally address the question of whether we should be intensifying systemic therapy for our patients with mHSPC by adding 2 drugs to ADT.

Until the results from this study are available, my recommendation is to choose either docetaxel or one of the AR-signaling therapies for intensification of systemic treatment with ADT in mHSPC, as I described above.

Provided by the USF Health in partnership with Clinical Care Options.

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