The topic of metastatic castration-sensitive prostate cancer has been on the forefront of clinical research in prostate cancer for many years now. In 2017, and again in 2019, I wrote Clinical Trials Portal articles on the topic of metastatic castration-sensitive prostate cancer, summarizing the key ongoing trials during those times.1, 2 We now know that early treatment intensification with the addition of either docetaxel, abiraterone acetate, enzalutamide or apalutamide to androgen deprivation therapy (ADT) offers a significant overall survival benefit. Docetaxel is the only agent that may have questionable benefit for low volume metastatic prostate cancer, with benefit perhaps being restricted to high-volume metastatic disease only, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis.3
Yet the question of “triple therapy” with ADT, docetaxel and a novel hormonal agent, also known as “chemohormonal therapy,” remains. The TITAN trial demonstrated overall survival benefit of apalutamide when added to ADT, however, the trial was amended after the CHAARTED trial resulted, to allow inclusion of patients who received docetaxel chemotherapy.4 As a result, the TITAN trial ultimately enrolled only 11% of patients with prior exposure to docetaxel chemotherapy. Similarly, the ARCHES trial recently confirmed overall survival benefit to enzalutamide when added to ADT.5 In the ARCHES trial, approximately 18% of the population had received prior docetaxel. Due to small sample sizes of patients who had received both docetaxel and novel hormonal agents in these two above trials, the field has not able to discern whether the concept of “triple therapy” offers significant survival benefit or not.
The ENZAMET trial clearly demonstrated that enzalutamide offers an overall survival benefit for patients with metastatic castration-sensitive prostate cancer.6 Unlike the other above trials, 45% of patients in the ENZAMET trial patients received docetaxel, hence there was more statistical power to make a statement about the addition of enzalutamide to ADT in this trial. The results confirmed that although enzalutamide with ADT and docetaxel offered superior radiographic progression free survival compared to ADT plus docetaxel, it did not provide overall survival benefit. Surprisingly, there were actually more docetaxel-related adverse events in the ADT plus docetaxel plus enzalutamide combination arm.
The discussion now runs deeper with the PEACE-1 data recently being presented at the European Society of Medical Oncology in September 2021. This was a phase 3 trial with a 2X2 factorial design in men with de novo metastatic castration-sensitive prostate cancer.7 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. The same stratification factors were adjusted for with the additional factor of docetaxel receipt to generate the hazard ratio for the entire population. Although this data is very exciting and promising the trial design and analysis from PEACE-1 has complexity.
As someone who has not read the entire final manuscript, understanding the exact pre-specified statistical design for the PEACE-1 trial design will be important. For example, the benefit of adding radiation to the prostate is still not definitively clear. Although these sorts of issues should work themselves out with the randomization, and I anticipate there will be more data forthcoming on this topic. Regardless, it is not unreasonable to consider ADT with docetaxel and abiraterone as a potential standard of care, especially for patient populations who are fit and wish to be aggressive. The previous finding of no survival benefit of adding enzalutamide to ADT plus docetaxel in the ENZAMET trial makes this PEACE-1 finding of survival benefit of adding abiraterone to ADT plus docetaxel somewhat curious. The pending ARASENS trial (NCT02799602) results may lend additional supportive data to “triple therapy,” since it is a pre-specified randomization of ADT plus docetaxel with or without darolutamide, for the entire trial population.
The question remains if we have pushed our combination trials with chemohormonal agents as far as they can take us for patients with metastatic castration-sensitive prostate cancer. There are still novel hormonal agent, like darolutamide or relugolix, that have yet to be tested alone and in novel combinations. Additionally, chemohormonal approaches with agents like cabazitaxel and carboplatin also warrant earlier evaluation in this disease state. Other approaches using immune-oncology agents, PARP inhibitors, radiopharmaceuticals and others for metastatic castration-sensitive prostate cancer will be explored in future Clinical Trials Portal articles. For the purposes of this discussion on chemohormonal therapy, please see below for details on select ongoing trials that utilize novel hormonal, chemotherapy and chemohormonal strategies.
Highlighted Trials with Novel Hormonal Agents and with Chemohormonal Therapy for metastatic castration-sensitive prostate cancer
- ARASEC – Phase 2 trial of ADT + Darolutamide (NCT05059236)
- ARANOTE – Randomized phase 3 trial of ADT +/- Darolutamide (NCT04736199)
- Phase 1 trial of Relugolix in combination with either abiraterone acetate or docetaxel (NCT04666129)
- Phase 2 trial of combination apalutamide and abiraterone acetate after 6 prior cycles of docetaxel (NCT04267887)
- CASCARA – Phase 2 trial of carboplatin with cabazitaxel followed by abiraterone with ADT (NCT03934840)
- Phase 2 trial of abiraterone acetate and apalutamide (NCT03821792)
- Yu EY. "Another Advance in Metastatic Hormone-Sensitive Prostate Cancer May Change Standard of Care Options but Not Attitude Toward Clinical Trials." Urotoday Clinical Trials Portal. On-line: July 14, 2017.
- Yu EY. "Enzalutamide and Apalutamide Now Offer Survival Benefit for Patients with Metastatic Castration-Sensitive Prostate Cancer, But How Do Things Change Now and What Should We Be Doing Next?" Urotoday Clinical Trials Portal. On-line: June 12, 2019.
- Kyriakopoulos CE et al. "Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial." J Clin Oncol (2018): 36:1080-7.
- Chi KN et al. "Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer." N Engl J Med (2019): 381:13-24.
- Armstrong AJ et al. "Final overall survival (OS) analysis from ARCHES: A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC)". Ann Oncol (2021): 32 (suppl_5):S1283-S1346; Abstract LBA25.
- Davis ID et al. "Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer". N Engl J Med (2019): 381:121-31.
- Fizazi K et al. "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; Abstract LBA5_PR.
Apalutamide Confirms Overall Survival Benefit at 44-Months in Metastatic Castration-Sensitive Prostate Cancer - The TITAN Study - Neeraj Agarwal
Overall Survival Results of PEACE-1 a Phase 3 Trial in Men With De Novo Metastatic Castration-Sensitive Prostate Cancer (mCSPC) – Karim Fizazi
The Efficacy of Enzalutamide + ADT vs Placebo + ADT in Patients Who Received Prior Antiandrogen Therapy in the ARCHES Study – Neal Shore