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Hormonal Intensification Should Start at the Low-risk Stage in Metastatic Prostate Cancer

Open AccessPublished:September 28, 2022DOI:https://doi.org/10.1016/j.euros.2022.05.015

      Abstract

      The treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has dramatically evolved. Monotherapy androgen deprivation therapy (ADT) with testosterone suppression alone is no longer the standard of care as multiple global phase 3 trials of different combinatorial strategies have been clinically and statistically successful and the combinations have been incorporated into guidelines on advanced prostate cancer. For appropriate patients, clinicians should consider combining ADT with docetaxel or an androgen receptor pathway inhibitor, or possibly with both. Shared patient-physician decision-making mandates a review of the level 1 evidence supporting the optimization and intensification of combination therapy for patients with mHSPC. Here we discuss the evidence underscoring intensification strategies as the standard of care for low-volume, low-risk mHSPC.

      Patient summary

      We discuss treatment strategies for men with metastatic prostate cancer. Combinations of androgen deprivation therapy (ADT) and drugs that inhibit the androgen receptor pathway are superior to ADT alone and prolong survival in patients with metastatic hormone-sensitive prostate cancer.

      Keywords

      The terminology for low-volume and low-risk staging of prostate cancer (PC) stems from two landmark trials, LATITUDE [
      • Fizazi K.
      • Tran N.P.
      • Fein L.
      • et al.
      Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.
      ] and CHAARTED [
      • Sweeney C.J.
      • Chen Y.H.
      • Carducci M.
      • et al.
      Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.
      ], which analyzed the efficacy of abiraterone acetate plus prednisone (AAP) in prolonging overall survival (OS) in men with metastatic hormone-sensitive PC (mHSPC). High risk was defined in the LATITUDE trial as meeting two of the following three criteria: a Gleason score of ≥8, three or more bone lesions, and the presence of visceral metastasis [
      • Fizazi K.
      • Tran N.P.
      • Fein L.
      • et al.
      Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.
      ]. In the CHAARTED trial, high-volume disease was defined as the presence of visceral metastasis and/or four or more bone lesions, with one or more outside the vertebral bodies or pelvic bones [
      • Sweeney C.J.
      • Chen Y.H.
      • Carducci M.
      • et al.
      Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.
      ]. Following these two successful trials in mHSPC, subgroup analyses comparing low-risk versus high-risk risk and low-risk versus high-volume PC have been performed for the well-designed and -conducted, multiarm, multistage STAMPEDE trial platform, along with other global trials evaluating combination therapy involving androgen deprivation therapy (ADT) with either enzalutamide (ENZA) or apalutamide (APA). AAP, ENZA, and APA have received international regulatory approval for combination with ADT for low-risk, low-volume mHSPC, as well as for patients with high-risk and/or high-volume mHSPC [
      • Sweeney C.J.
      • Chen Y.H.
      • Carducci M.
      • et al.
      Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.
      ]. A summary of the published trials and oncologic outcomes for men with low-risk, low-volume mHSPC treated with hormonal intensification strategies is presented in Table 1 and Figure 1.
      Table 1Summary of trials and oncologic outcomes for men with metastatic hormone-sensitive prostate cancer
      PhaseInterventionControl armTotal patientsLV mHSPC, n (%)LV definition
      CHAARTED criteria for LV versus high-volume disease: high-volume disease is defined as the presence of visceral metastasis and/or four or more bone lesions with one or more outside of the vertebral bodies or pelvic bone.
      Primary endpoint(s)
      Abiraterone
      STAMPEDE NCT00268476 post hoc analysis3Abiraterone (1000 mg) plus prednisone (5 mg) + ADT (trial arm G)ADT alone

      (trial arm A)
      2751 (901 included in analysis)402 (14.6%)CHAARTED criteriaOS: HR 0.64 (95% CI 0.42–0.97)

      3-yr OS: 83% vs 77%

      FFS: HR 0.26 (95% CI 0.19–0.36)

      3-yr FFS: 74% vs 32%
      Enzalutamide
      ARCHES NCT026778963Enzalutamide (160 mg daily) + ADTPlacebo + ADT1150423 (36.8%)CHAARTED criteriarPFS: HR 0.25 (95% CI 0.14–0.46)
      ENZAMET NCT024464053Enzalutamide (160 mg daily) + ADTNSAA + ADT1125272 (24.2%)CHAARTED criteriaOS: HR 0.43 (95% CI 0.26–0.72)
      ENZAMET NCT02446405 post hoc analysis3Enzalutamide (160 mg daily) + ADTNSAA + ADT1125205 (18.2%)– M0 at diagnosis

      – CHAARTED criteria
      OS: HR 0.40 (95% CI 0.16–0.97)

      3-yr OS: 92% vs 83%
      Apalutamide
      TITAN NCT024893183Apalutamide (280 mg daily) + ADTPlacebo + ADT1052392 (37.2%)CHAARTED criteriaOS: HR 0.52 (95% CI 0.35–0.79)
      LV = low volume; mHSPC = metastatic hormone-sensitive prostate cancer; ADT = androgen deprivation therapy; NSAA = nonsteroidal antiandrogen; OS = overall survival; rPFS = radiographic progression-free survival; FFS = failure-free survival; HR = hazard ratio; CI = confidence interval.
      a CHAARTED criteria for LV versus high-volume disease: high-volume disease is defined as the presence of visceral metastasis and/or four or more bone lesions with one or more outside of the vertebral bodies or pelvic bone.
      Figure thumbnail gr1
      Fig. 1Forest plot of hazard ratios for overall survival and progression-free survival in subgroups from the ARASENS, ARCHES, ENZAMET, STAMPEDE, and TITAN trials.
      The STAMPEDE trial assessed the benefit of early initiation of AAP in addition to ADT in men with locally advanced or metastatic PC starting ADT for the first time [
      • James N.D.
      • de Bono J.S.
      • Spears M.R.
      • et al.
      Abiraterone for prostate cancer not previously treated with hormone therapy.
      ]. A post hoc analysis [
      • Hoyle A.P.
      • Ali A.
      • James N.D.
      • et al.
      Abiraterone in “high-” and “low-risk” metastatic hormone-sensitive prostate cancer.
      ] of STAMPEDE evaluated men with low-volume, low-risk mHSPC defined according to CHAARTED [
      • Sweeney C.J.
      • Chen Y.H.
      • Carducci M.
      • et al.
      Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.
      ] and LATITUDE [
      • Fizazi K.
      • Tran N.P.
      • Fein L.
      • et al.
      Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.
      ] criteria. The group with low-risk mHSPC who received AAP had better OS (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.44–0.98) and failure-free survival (FFS; HR 0.25, 95% CI 0.17–0.33) in comparison to ADT alone [
      • Hoyle A.P.
      • Ali A.
      • James N.D.
      • et al.
      Abiraterone in “high-” and “low-risk” metastatic hormone-sensitive prostate cancer.
      ]. In addition, men with low-risk mHSPC who received AAP had higher skeletal-related event (SRE)-free survival (HR 0.31, 95% CI 0.18–0.54), longer progression-free survival (PFS; HR 0.33, 95% CI 0. 23–0.48), and lower PC-specific mortality (HR 0.51, 95% CI 0.31–0.84) [
      • Hoyle A.P.
      • Ali A.
      • James N.D.
      • et al.
      Abiraterone in “high-” and “low-risk” metastatic hormone-sensitive prostate cancer.
      ].
      The ARCHES trial [
      • Armstrong A.J.
      • Szmulewitz R.Z.
      • Petrylak D.P.
      • et al.
      ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer.
      ] compared ENZA plus ADT to ADT alone for men with mHSPC. ENZA improved radiographic PFS in the subgroups of men with low-volume (HR 0.25, 95% CI 0.14–0.46) and low-risk disease (HR 0.42, 95% CI 0.28–0.62). Men receiving ENZA also had prolonged OS (HR 0.66, 95% CI 0.52–0.81), although subgroup-specific data have not been reported [
      • Armstrong A.J.
      • Szmulewitz R.Z.
      • Petrylak D.P.
      • et al.
      ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer.
      ,
      • Azad A.A.
      • Armstrong A.J.
      • Alcaraz A.
      • et al.
      Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk.
      ]. In the ENZAMET trial, men with mHSPC were randomized to receive ENZA plus ADT or a nonsteroidal antiandrogen drug (bicalutamide, nilutamide, or flutamide) plus ADT. ENZA was associated with better OS (HR 0.43, 95% CI 0.26–0.72) and PFS (HR 0.30, 95% CI 0.22–0.43) among men with low-volume disease [
      • Davis I.D.
      • Martin A.J.
      • Stockler M.R.
      • et al.
      Enzalutamide with standard first-line therapy in metastatic prostate cancer.
      ].
      Similar to previous results with ENZA and AAP, hormonal intensification with APA in the TITAN trial [
      • Chi K.N.
      • Chowdhury S.
      • Bjartell A.
      • et al.
      Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study.
      ,
      • Chi K.N.
      • Agarwal N.
      • Bjartell A.
      • et al.
      Apalutamide for metastatic, castration-sensitive prostate cancer.
      ] delayed disease progression (radiographic PFS [rPFS]: HR 0.37, 95% CI 0.22–0.57) and was associated with better OS (HR 0.52, 95% CI 0.35–0.79) among men with low-volume mHSPC. While there was a clear statistical median OS benefit for men with high-risk disease (HR 0.57, 95% CI 0.45–0.73), OS outcomes favored the use of APA in low-risk disease but did not achieve statistical significance (HR 0.76, 95%CI 0.54–1.07).
      In addition, ongoing trials are investigating other opportunities for hormonal intensification in the prostate cancer continuum, including patients with biochemical recurrence (EMBARK) and concomitant triple-agent intensification, such as the PEACE-1 [
      • Fizazi K.
      • Foulon S.
      • Carles J.
      • et al.
      Abiaterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2×2 factorial design.
      ] and ARASENS [
      • Smith M.R.
      • Hussain M.
      • Saad F.
      • et al.
      Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.
      ] trials. PEACE-1 is investigating the combination of standard-of-care treatment (ADT or ADT + docetaxel) ± radiotherapy and ± AAP for men with de novo mHSPC [
      • Fizazi K.
      • Foulon S.
      • Carles J.
      • et al.
      Abiaterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2×2 factorial design.
      ]. Its unique 2 × 2 factorial design allows assessment of triplet therapy (ADT + docetaxel + AAP) between groups with high-volume and low-volume disease. Men with high-volume disease benefited considerably from triplet therapy, with statistically better rPFS (HR 0.47, 95% CI 0.30–0.72) and OS (HR 0.72, 95% CI 0.55–0.95) in comparison to men with low-volume disease (rPFS: HR 0.58, 95% 0.29–1.15; OS: HR 0.83, 95% CI 0.50–1.39). The ARASENS trial is assessing a different triplet combination therapy (ADT + docetaxel ± darolutamide) for men with mHSPC [
      • Smith M.R.
      • Hussain M.
      • Saad F.
      • et al.
      Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.
      ]. While data comparing low-volume to high-volume disease have not yet been analyzed, the cohort experienced a striking improvement in OS (HR 0.68, 95% CI 0.57–0.80) and in the median time to castration resistance (HR 0.36, 95% CI 0.30–0.42) with the addition of darolutamide. Furthermore, the frequency of grade 3 or 4 adverse events was similar between the two groups (63.5% placebo vs 66.1% darolutamide) [
      • Smith M.R.
      • Hussain M.
      • Saad F.
      • et al.
      Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.
      ].
      ADT monotherapy is no longer the preferred strategy for men with mHSPC. The data on dual and triplet hormonal intensification for men with mHSPC demonstrate clear improvements in oncologic outcomes, including survival, disease progression, time to pain, symptomatic skeletal events, and time to castration resistance, while patient quality-of-life parameters were maintained [
      • Armstrong A.J.
      • Szmulewitz R.Z.
      • Petrylak D.P.
      • et al.
      ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer.
      ,
      • Davis I.D.
      • Martin A.J.
      • Stockler M.R.
      • et al.
      Enzalutamide with standard first-line therapy in metastatic prostate cancer.
      ]. Importantly, shared decision-making with patients in the early stage of metastatic disease is essential, including a discussion of alternatives to hormone intensification such as stereotactic body radiation therapy to low-volume metastatic sites via a clinical trial or primary prostate cancer radiation for low-volume mHSPC [
      • Parker C.C.
      • James N.D.
      • Brawley C.D.
      • et al.
      Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.
      ]. It must be recognized that the ongoing and future applicability of therapeutic regimens and the definition of low-volume mHSPC may change as more accurate imaging technology such as prostate-specific membrane antigen positron emission tomography becomes more accessible.
      Conflicts of interest: Seyed Behzad Jazayeri, Lauren Folgosa Cooley, and Abhishek Srivastava have nothing to disclose. Neal Shore has a consulting/advisory board relationship with AbbVie, Astellas, AstraZeneca, Bayer, Janssen, Merck, Myovant, Pfizer, and Tolmar.

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      Linked Article

      • Treatment Intensification for Low-risk Metastatic Hormone-sensitive Prostate Cancer: The Time Is Now
        European Urology Open ScienceVol. 45
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          The treatment landscape for metastatic hormone-sensitive prostate (mHSPC) has undergone dramatic changes within the past decade. Historically, androgen deprivation therapy (ADT) with or without a first-generation antiandrogen was the standard of care for patients with mHSPC, with treatment intensification including chemotherapy and androgen receptor signaling inhibitors (ARSIs) reserved for individuals with metastatic castration-resistant prostate cancer (mCRPC). In 2015, results from the landmark phase 3 CHAARTED [1] and STAMPEDE [2] trials catapulted us into the modern era of treatment intensification for patients with mHSPC.
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