Triple Combination Therapy With Chemohormonal Approaches: Paving a Path Forward in Various Disease States With Newer Agents and Even More Treatment Intensification

I recently wrote about “triple combination therapy” with androgen deprivation therapy (ADT), docetaxel, and a novel hormonal agent a few months ago.1  In that article, I described a list of enrolling trials utilizing either novel hormonal, chemotherapy and/or chemohormonal strategies for patients with metastatic castration-sensitive prostate cancer.  Yet, we are fortunate, as a field, that the landscape is rapidly changing as new advances continue to be reported.

Around the time of that Clinical Trials Portal article, the PEACE-1 data had just been presented at the European Society of Medical Oncology in September 2021.2  This was a phase 3 trial with a 2X2 factorial design in men with de novo metastatic castration-sensitive prostate cancer.  The randomization was 1:1:1:1 for standard of care (SOC), SOC plus abiraterone acetate, SOC plus radiotherapy to the prostate, or SOC plus abiraterone acetate plus radiotherapy to the prostate.  SOC was initially ADT and eventually amended to ADT plus docetaxel; the ADT plus docetaxel group was a key focus of the presentation at ESMO.  All patients who received ADT plus docetaxel were used as control, including some who were in the radiation group, and others who were not in the radiation group.  Approximately 60% of the overall patient population received docetaxel.  The co-primary endpoints of radiographic progression free survival (median 4.5 vs. 2.0 years; HR 0.50, 95% CI 0.40-0.62, p<0.0001) and overall survival (median Not evaluable vs. 4.4 years; HR 0.75, 95% CI 0.59-0.95, p=0.017) in the ADT with docetaxel +/- radiation therapy population was in favor of addition of abiraterone for both endpoints.  Note that prior radiation therapy, type of castration, performance status and metastatic burden were adjusted for in the hazard ratios above.  Overall abiraterone added survival benefit to the entire population, resulting in median survival of 5.7 vs. 4.7 years; HR 0.82, 95% CI 0.69-0.98, p=0.030.   

We now have additional data, presented at the Genitourinary Cancers Symposium and published simultaneously in the New England Journal of Medicine.3  The ARASENS trial enrolled patients eligible to receive docetaxel to a pre-specified randomization of ADT plus docetaxel with darolutamide or placebo.  The primary endpoint was met, in favor of darolutamide for overall survival (HR 0.68; 95% CI 0.57-0.80; p<0.001).  Adverse events were similar in the two groups.

In the ARASENS trial, all patients received ADT + docetaxel, although there were no designations for the “high-volume” and “low-volume” subsets from CHAARTED.4  However, ARASENS enrolled 86.1% of patients with de novo metastatic prostate cancer, a patient population generally felt to have a more limited prognosis.  The likelihood is that the number of patients who met the CHAARTED-defined “low-volume” and/or LATITUDE5-defined “low-risk” patients will be uncovered and found to be rare with future post-hoc analyses from the ARASENS trial.

It seems likely that a new standard of care for patients eligible for docetaxel chemotherapy, certainly those with “high-volume” or “high-risk” disease, will begin to receive chemohormonal therapy with ADT, docetaxel and either darolutamide or abiraterone acetate.  Yet there are still valid questions surrounding “triple combination therapy.”  The first is whether these combinations for metastatic castration-sensitive prostate cancer should be studied together in greater depth for metastatic castration-resistant prostate cancer to improve outcomes.  Second, is whether there are other novel hormonal therapies or chemotherapies that should be studied as a substitute for one of the current agents above, perhaps with potential for reduction of toxicity.  Finally, is whether adding other local or systemic therapies to the “triple combination therapies” above might contribute significant efficacy benefits.  There are some ongoing accruing trials now that address one or more of the above questions.  Please see below for details of some of these select ongoing relevant trials.

Highlighted Trials with Triple Combination Therapy for Prostate Cancer

  • IP2-ATLANTA – Randomized Phase 2 trial of standard of care (SOC) therapy (including triple combination therapy) vs. SOC with minimally invasive ablative therapy (e.g. HIFU or cryotherapy) vs. SOC with radical therapy (e.g. radical prostatectomy or radiation therapy) (NCT03763253)
  • SWOG 1802 – Randomized phase 3 trial of standard systemic therapy with or without definitive local treatment (may include metastasis directed therapy) (NCT03678025)
  • First Strike, Second Strike – Phase 2A trial of LHRH therapy, novel hormonal agent, docetaxel and Tislelizumab (anti-PD-1 antibody) for high risk metastatic castration-sensitive prostate cancer (NCT05189457)
  • CASCARA – Phase 2 trial of carboplatin with cabazitaxel followed by abiraterone with ADT for metastatic castration sensitive prostate cancer (NCT03934840)
  • Phase 2 trial of SHR3680 (novel pure androgen receptor antagonist) with docetaxel for metastatic castration-resistant prostate cancer (NCT04603833)
  • ECOG/ACRIN – Randomized phase 2 trial of abiraterone + antiandrogen therapy with or without cabazitaxel in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (NCT03419234)

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References

1. Yu EY. "Metastatic Castration-Sensitive Prostate Cancer, The Advances Keep Coming With Chemohormonal Therapy." Urotoday Clinical Trials Portal. On-line: November 2021.
2. Fizazi K et al. LBA5_PR - A phase III trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: Overall survival with abiraterone acetate plus prednisone in PEACE-1. Ann Oncol (2021); 32 (suppl_5):S1283-S1346.
3. Smith, M., Hussain M., Saad F., Citation: Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. New England Journal Of Medicine. doi: 10.1056/nejmoa2119115
4. Sweeney CJ et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015; 373:737-46.
5. Fizazi K et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377:352-60.
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