Metastatic Hormone-Sensitive Prostate Cancer

*****These notes provide an overview of the treatments in metastatic castrate-sensitive prostate cancer. For notes on selecting treatment for metastatic castrate-sensitive prostate cancer, please see the 2020 CUA Guideline Notes on Metastatic Castrate-Sensitive Prostate Cancer*****

Background

• Incidence of metastatic hormone-sensitive prostate cancer (mHSPC) has been increasing in recent years
• Previously, ADT was the only treatment option for mHSPC. Recently, treatment options that were used in the castrate-resistant stages of the disease have been shown to have benefit in the hormone-sensitive stage
• Options:
  • ADT with one of the following (6):
    • Hormonal therapy (4)
      • Inhibition of androgen synthesis: abiraterone
      • Androgen-receptor antagonists: enzalutamide, apalutamide, darolutamide
    • Chemotherapy: docetaxel
    • Radiation

Hormonal therapy

Inhibition of Androgen Synthesis

Abiraterone

• STAMPEDE (James et al. NEJM 2017)
  • Population: 1917 patients had prostate cancer that was newly diagnosed and metastatic, node-positive, or high-risk locally advanced prostate cancer (with at least two of following: a tumor stage of T3 or T4, a Gleason score of 8 to 10, and a PSA level ≥40 ng per milliliter) or disease that was previously treated with radical surgery or radiotherapy and was now relapsing with high-risk features (in men no longer receiving therapy, a PSA level >4 ng per milliliter with a doubling time of <6 months, a PSA level >20 ng per milliliter, nodal or metastatic relapse, or <12 months of total ADT with an interval of >12 months without treatment)
  • Randomized to ADT +/- abiraterone + prednisone
  • Results:
    • Overall and failure-free survival significantly improved in abiraterone + ADT
  • James, Nicholas D., et al. "Abiraterone for prostate cancer not previously treated with hormone therapy." New England Journal of Medicine 377.4 (2017): 338-351.

• LATITUDE (Fizazi et al. 2017)
  • Population: 1199 patients with high-risk, metastatic, hormone-sensitive prostate cancer
    • High-risk required 2/3 high-risk factors:
      1. Visceral metastasis
      2. ≥ 3 bone lesions
         • Recall, CHAARTED was ≥4 bone lesions with ≥ 1 beyond the vertebral bodies and pelvis
      3. Gleason score ≥ 8
  • Randomized to ADT +/- abiraterone + prednisone
  • Primary end points: OS and radiographic progression-free survival
  • Results:
    • Median follow-up: 30 months
    • OS significantly improved in the abiraterone group (median not reached abiraterone vs. 34.7 months placebo) (HR 0.62)
    • Median length of radiographic progression-free survival significantly longer in the abiraterone group (33.0 months vs. 14.8 months placebo, HR 0.47)
  • Fizazi, Karim, et al. "Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer." New England Journal of Medicine 377.4 (2017): 352-360.

Androgen-receptor Antagonists

Enzalutamide

• ENZAMET (Davis et al. NEJM 2019)
  • Population: 1125 patients with metastatic, hormone-sensitive prostate cancer
  • Randomized to enzalutamide vs. placebo
  • Primary outcome: OS
  • Secondary outcomes: progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events
  • Results:
    • Median follow-up: 34 months
    • OS significantly improved in enzalutamide arm (HR 0.67, 95% CI 0.52-0.86; absolute risk difference at 3-years: 8% (80% enzalutamide vs. 72% placebo)
    • PSA-PFS and clinical PFS significantly improved in enzalutamide arm
    • Fatigue and seizures more common in enzalutamide group
  • Davis, Ian D., et al. "Enzalutamide with standard first-line therapy in metastatic prostate cancer." New England Journal of Medicine 381.2 (2019): 121-131.
• ARCHES (Armstrong et al. JCO 2019)
  • Population: 1150 patients with metastatic, hormone-sensitive prostate cancer
  • Randomized to enzalutamide vs. placebo
  • Primary outcome: radiographic progression-free survival
  • Results:
    • Significantly improved radiographic progression-free survival with enzalutamide (HR, 0.39; 95% CI 0.30-0.50)
      • Improved in high-volume and low-volume disease
  • Armstrong, Andrew J., et al. "ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer." Journal of Clinical Oncology 37.32 (2019): 2974-2986.

Apalutamide

• TITAN (Chi et al. NEJM 2019)
  • Population: 525 patients with metastatic, hormone-sensitive prostate cancer
  • Randomized to apalutamide vs. placebo
  • Primary outcome: radiographic progression-free and overall survival
  • Results:
    • Significantly improved radiographic progression-free and overall survival with apalutamide
  • Chi, Kim N., et al. "Apalutamide for metastatic, castration-sensitive prostate cancer." New England Journal of Medicine 381.1 (2019): 13-24.

Darolutamide

• ARASENS (Smith et al. NEJM 2022)
  • Population: 1306 patients with metastatic, hormone-sensitive prostate cancer
  • Randomized to ADT + docetaxel +/- darolutamide
  • Primary outcome: overall survival
  • Results
    • Significantly improved overall survival with darolutamide
  • Smith, Matthew R., et al. "Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer." New England Journal of Medicine (2022).

Chemotherapy

Docetaxel

Mechanism of Action

• Taxane class of chemotherapy
• Inhibits microtubule assembly resulting in cell cycle arrest

Adverse Events

1. Alopecia
2. Anemia
3. Diarrhea
4. Dyspnea
5. Fluid retention
6. Nausea/vomiting
7. Neuropathy
8. Neutropenia and infections
9. Thrombocytopenia

Landmark Trials

• CHAARTED (Sweeney et al. NEJM 2015)
  • Population: 790 men with metastatic, hormone-sensitive prostate cancer
  • Randomized to ADT +/- docetaxel
  • Stratified analysis by disease burden: high vs. low volume
    • High-volume:
      • Visceral mets or
      • ≥4 bone lesions with ≥ 1 beyond the vertebral bodies and pelvis
    • Low-volume: all others
  • Results:
    • Median follow-up: 28.9 months
    • OS improved by 13.6 months in ADT + docetaxel arm (median OS 57.6 ADT + docetaxel vs. 44.0 months ADT, HR 0.61) in non-stratified analysis
      • In stratified analysis by high vs. low volume disease, benefit only significant on high-volume disease
  • Sweeney, Christopher J., et al. "Chemohormonal therapy in metastatic hormone-sensitive prostate cancer." New England Journal of Medicine 373.8 (2015): 737-746.
  • 2019 NCCN guidelines recommend ADT and docetaxel for patients with M1, castration-naïve disease; ADT as monotherapy recommended for asymptomatic patients with metastatic disease and life expectancy ≤ 5 years
• STAMPEDE (James et al. Lancet 2016)
  • Multi-arm, multi-stage design
  • Population: 2692 men with newly diagnosed as metastatic, node positive, or high-risk locally advanced prostate cancer (with ≥2 of T3/4, Gleason score of 8–10, and PSA ≥40 ng/mL); or previously treated with radical surgery, radiotherapy, or both and relapsing with high-risk features and were starting first-line long-term hormone therapy
    • Of all patients, majority (≈60%) were newly diagnosed with metastasis at the time of diagnosis , some were newly diagnosed with M0 disease, and few patients previously treated.
    • (In contrast to CHAARTED, this trial included patients with non-metastatic disease. Similar to CHAARTED, this trial was in hormone-sensitive patients)
  • Randomized to standard of care (ADT x 2 years), SOC + zoledronic acid, SOC + docetaxel, and SOC + ZA + docetaxel.
    • Radiotherapy, at 6–9 months after randomisation, was encouraged for patients with N0M0 disease, until November, 2011, then mandated; radiotherapy was optional for patients with N+M0 disease; staging
    • Docetaxel (75 mg/m²) was given for six 3-weekly cycles with prednisolone (10 mg) daily,
  • The definitive and intermediate primary outcome measures were overall survival and failure-free survival, respectively.
    • Failure-free survival, which is commonly used to drive decisions in the clinic, was selected because it is on the causal pathway to death from prostate cancer and was not required to be a surrogate for overall survival. It was defined as time from randomisation to first evidence of at least one of: biochemical failure; progression either locally, in lymph nodes, or in distant metastases; or death from prostate cancer.
  • Results:
    • Median follow-up: 43 months
    • Majority (71-76%) of patients assigned to docetaxel completed the 6 cycles
    • SOC + docetaxel improved OS by 10 months (median OS in SOC + doce 81 months vs. SOC 71 months, HR 0.78). SOC + ZA + doce has improved survival compared to SOC but no difference with SOC + doce. SOC + ZA did not improve survival compared to OS, suggesting that ZA as an agent did not improve survival beyond that attributed to doce.
    • Failure-free survival, skeletal-related events, and cancer-specific survival also improved in patients receiving docetaxel.
    • Febrile neutropenia and neutropenia were the most common adverse events in the docetaxel arm
    • James, Nicholas D., 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." The Lancet 387.10024 (2016): 1163-1177.

Radiation

• STAMPEDE 2018 (Parket et al. Lancet 2018)
  • Population: 1061 patients with newly diagnosed, with no previous radical treatment, metastatic, hormone-sensitive prostate cancer
  • Randomized to radiotherapy vs. SOC
  • Primary outcome: OS
  • Secondary outcomes: failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival.
  • Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden (high vs. low-volume based on CHAARTED definition (see above) and radiotherapy schedule.
  • Results:
    • Median follow-up: 37 months
    • No benefit in OS (HR 0.92, 95% CI 0.80–1.06)
    • Significantly improved failure-free survival in radiotherapy group (HR 0.76, 95% CI 0.68–0·84)
    • Subgroup analysis:
      • OS significantly improved in low-metastatic burden group (HR 0.68, 95% CI 0.52–0.90) but not high-metastatic burden group (HR 1.07 95% CI 0.90–1.28)
      • Failure-free survival significantly improved in both subgroups
  • Parker, Christopher C., et al. "Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial." The Lancet 392.10162 (2018): 2353-2366.

Questions

1. Describe the CHAARTED trial. What was the CHAARTED definition of high-volume metastasis?
2. What are the treatment options and which trails support them for: metastatic vs. non-metastatic castrate-sensitive vs. castrate-naiive prostate cancer?

Answers

1. Describe the CHAARTED trial. What was the CHAARTED definition of high-volume metastasis?
   • Population: 790 men with metastatic castration-sensitive disease
     • Stratified by high-volume (visercal metastasis or ≥4 bone lesions with ≥ 1 beyond the vertebral bodies and pelvis)
   • Randomized to ADT vs. ADT + docetaxel
   • Primary outcome: OS
   • Results:
     • Median follow-up: 29 months
     • Patients receiving chemo had improved OS by 14 months, with benefit only seen in high-volume in stratified analysis
2. What are the treatment options and which trails support them for: metastatic vs. non-metastatic castrate-sensitive vs. castrate-naiive prostate cancer?

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 120