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Metastatic Castration-Sensitive Prostate Cancer, If Treatment Intensification Is the Standard, Who and How Can We Treatment Deintensify?

Metastatic castration-sensitive prostate cancer (mCSPC) is a disease state where the benefits of treatment intensification are clear. Androgen receptor pathway inhibitors (ARPIs) offer overall survival benefit when added to conventional androgen deprivation therapy (ADT). The specific ARPIs include abiraterone acetate,1,2 enzalutamide,3,4 and apalutamide.5 Docetaxel chemotherapy offers survival benefit for patients with high volume disease,6 and either abiraterone7 or darolutamide8 offer survival benefit when added to ADT and docetaxel for patients, especially for those with de novo and high-volume mCSPC.

If you rewind the clock further back, we did not always know that lifelong, continuous ADT was necessary. The SWOG 9346 trial, using a non-inferiority trial design, established that intermittent ADT was not non-inferior to continuous ADT for patients with mCSPC.9 Yet, there may be specific details in that trial design that led to that outcome. For example, the treatment intervals were followed by ADT-free breaks until a PSA threshold of either 20 ng/mL or the individual patient’s baseline PSA value, whichever was lower, was reached before triggering the next ADT treatment cycle. Was 20 ng/mL too high of a threshold? Most notable is the fact that there was no prognostic treatment selection in the trial. Ideally, one would try to spare the patient clinical and financial toxicity with intermittent ADT if that patient was known to have a “good prognosis.” Yet, a “good prognosis” was only defined subsequently from this trial and other future treatment intensification trials by absolute PSA value at the 3-12-month time frame in response to ADT.10-12

It is logical that if a patient has aggressive enough disease characteristics and is healthy enough to live long enough to die of prostate cancer, treatment intensification is likely to add additional survival benefit. However, if a patient has significant competing causes of mortality, combined with good prostate cancer biology, shouldn’t we, as a field, be working hard to treatment deintensify, with the goal of improved quality of life for those individuals?

It is well accepted that we need to identify better molecular prognostic markers; in the meantime, the absolute PSA value, in response to ADT, with or without treatment intensification, may still be the best prognostic marker to select those patients with indolent enough disease to consider treatment deintensification. Therefore, patients who have outstanding PSA declines, especially those who achieve an undetectable PSA, may be an ideal target population to study treatment deintensification.

The LIBERTAS phase 3 trial randomizes patients who achieve an undetectable PSA after 6 months of ADT plus apalutamide to either continuous treatment or intermittent ADT, while continuing apalutamide monotherapy. The key outcome measures include 18-month radiographic progression-free survival and percent change in severity of adjusted hot flash score at 18 months. Certainly, the latter is apt to be positive, as one of the key benefits of AR antagonist monotherapy is the decrease in hot flashes. This was shown in the EMBARK trial, although it is not clear that there are other quality of life benefits, as breast symptoms can be worse when LHRH therapy is withheld in the setting on AR antagonist use.13 Regardless, this trial is actively accruing and requires our attention.

Another trial, led by the ALLIANCE group through the National Cancer Trials Network (NCTN) is A-DREAM. This is a randomized phase 2 trial where patients receiving intensified ADT with an ARPI, if experiencing an outstanding PSA decline to treatment, will stop both ADT and ARPI intermittently and restart when PSA reaches 5 ng/mL or radiographic progression occurs. This trial has the advantage of “dealer’s choice” for the ARPI, picking a good prognosis population, a low PSA threshold to restart, and the cessation of all hormonal agents during off-treatment cycles. That said, will a phase 2 randomized trial be enough to offer a potentially new standard of care? If not, will the field have the appetite to start all over and commit enormous resources to a large randomized, phase 3 trial effort?

Finally, the HERO trial, leading to the regulatory approval of Relugolix, had a lower incidence of major cardiovascular events (MACE) compared to leuprolide.14 As a result, there is a phase 1 trial ongoing in combining Relugolix with either abiraterone, apalutamide, or docetaxel to see whether the incidence of adverse events is decreased.

Below, I highlight ongoing, actively accruing trials for patients with mCSPC, that offer promise for treatment deintensification and/or toxicity-sparing/quality of life benefit potential.

Highlighted potential toxicity sparing trials for patients with metastatic castration-sensitive prostate cancer

  • NCT05884398: LIBERTAS - randomized Phase 3 trial of Apalutamide with intermittent ADT vs. Apalutamide with continuous ADT
  • NCT05241860: A-DREAM – phase 2 trial of interrupting hormonal therapy for exceptional PSA responders
  • NCT04666129: Phase 1 trial of relugolix in mCSPC or mCRPC in combination with abiraterone, apalutamide or docetaxel
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Fizazi K, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377:352-60.
  2. James ND, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 2017; 377:338-51.
  3. Armstrong AJ, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2022; 40:1616-22.
  4. Davis ID, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019; 381:121-31.
  5. Chi KN, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2019; 381:13-24.
  6. Sweeney C, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015; 373:737-46.
  7. Fizazi K, et al. Abiraterone 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. Lancet 2022; 399:1695-1707.
  8. Smith MR, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med 2022; 386:1132-42.
  9. Hussain M, et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. N Engl J Med 2013; 368:1314-25.
  10. Hussain M, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006; 24:3984-90.
  11. Harshman LC, et al. Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone-Sensitive Prostate Cancer Treated With Androgen Deprivation With or Without Docetaxel. J Clin Oncol 2018; 36:376-82.
  12. Chowdhury S, et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol 2023; 34:477-85.
  13. Freedland SJ, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med 2023; 389:1453-65.
  14. Shore ND, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med 2020; 382:2187-96.