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Real-World Utilization of Treatment Intensification in Metastatic Hormone Sensitive Prostate Cancer: Are We Lacking Intensity?

Prostate cancer, while commonly diagnosed early in the disease state, remains the second leading cause of cancer mortality in the United States and Europe1 . Of the 1.3 million new annual diagnoses of prostate cancer, 6% of men have metastases at the time of diagnosis. Such patients are defined as having de novo or synchronous metastatic hormone sensitive prostate cancer (mHSPC).

Written by: Christopher J.D. Wallis, MD PhD, Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
References:
  1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
  2. Cancer Stat Facts: Prostate Cancer. National Cancer Institute. Available at https://seer.cancer.gov/statfacts/html/prost.html. Accessed: July 17, 2022.
  3. James ND, Sydes MR, Clarke NW, 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. Lancet. 2016;387(10024):1163-1177.
  4. Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N ENgl J Med. 2015;373:737-746.
  5. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New Engl J Med.. 2017;377(4):352-360.
  6. Hoyle AP, Ali A, James ND, et al. Abiraterone in “High-” and “Low-risk” Metastatic Hormone-sensitive Prostate Cancer. Eur Urol. 2018;76(6):719-728.
  7. Chi KN, 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. J Clin Oncol. 2021;39(2):2294-2303.
  8. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381(2):121-131.
  9. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37(32):2974-2986.
  10. Fizai K, Foulon S, Carles J, 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(10336):1695-1707.
  11. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-1142.
  12. Virgo KS, Rumble RB, de Wit R, et al. Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update. J Clin Oncol. 2021;39(11):1274-1305.
  13. Schaeffer E, Srinivas S, Antonarakis ES, et al. NCCN Guidelines Insights: Prostate Cancer, Version 1.2021. J Natl Compr Canc Netw. 2021;19(2):134-143.
  14. EAU Guidelines Prostate Cancer. https://uroweb.org/guidelines/prostate-cancer. Accessed on Oct 1, 2022.
  15. Ryan CJ, Ke X, Lafeuille M, et al. Management of Patients with Metastatic Castration-Sensitive Prostate Cancer in the Real-World Setting in the United States/ J Urol. 2021;206(6):1420-1429.
  16. Freedland SJ, Sandin R, Sah J, et al. Treatment patterns and survival in metastatic castration-sensitive prostate cancer in the US Veterans Health Administration. Cancer Med. 2021;10(23):8570-8580.
  17. Leith A, Ribbands A, Kim J, et al. Impact of next-generation hormonal agents on treatment patterns among patients with metastatic hormone-sensitive prostate cancer: a real-world study from the United States, five European countries and Japan. BMC Urol. 2022;22(1):33.
  18. Wallis CJD, Malone S, Cagiannos I, et al. Real-World Use of Androgen-Deprivation Therapy: Intensification Among Older Canadian Men With de Novo Metastatic Prostate Cancer. JNCI Cancer Spectr. 2021;5(6):pkab082.

 

The Current Landscape of Metastatic Hormone Sensitive Prostate Cancer: Treatment Utilization and Future Directions

Introduction

The treatment landscape of advanced prostate cancer continues to evolve, particularly over the last 5+ years. Although there are several treatment options, including both ADT-based doublet and triplet combinations, available for men with metastatic hormone sensitive prostate cancer (mHSPC) that have showed an OS benefit versus ADT alone, there remain several unaddressed questions. First, among the available options, which is to be preferred and for whom: head-to-head trials assessing treatment options are unavailable. There are many reasons for this, including the time involved for these trials to accumulate an appropriate event rate for OS outcomes, and the fact that the majority of these trials are industry-sponsored. As such, investigators have relied on unique statistical methods (such as network meta-analyses) and real-world observations to guide treatment planning in the setting of several efficacious treatment options. Second, real world studies have shown relatively poor uptake of these treatments with proven life-prolonging benefit. Third, despite the improvements seen with these studies, mCSPC remains a life-limiting diagnosis. Thus, there is a need for the development of novel treatment approaches: there are several exciting ongoing/planned clinical trials in the mHSPC disease space that will be reporting outcomes in the coming years.

Comparison of Approved Agents in mHSPC space

Given the multitude of approved agents in this disease space, multiple systematic reviews and network meta-analyses indirectly comparing the available agents have been performed. Because of a lack of head-to-head clinical trials, a network meta-analysis can be employed to perform an indirect comparison among intervention arms for trials that have the same control arm. In 2021, Mori et al. published in BJU International a network meta-analysis, which included 9 trials. The magnitude of OS benefit was greatest in those treated with abiraterone (HR: 0.83, 95% CI: 0.76-0.90), followed by enzalutamide (HR: 0.85, 95% CI: 0.73-0.99), and docetaxel (HR: 0.90, 95% CI: 0.82-0.98).1 These findings are consistent with those published by Wang et al. in JAMA Oncology who also demonstrated that abiraterone had the greatest OS benefit in mHSPC patients (HR:0.61, 95% CI: 0.54-0.70).2 Conversely, in 2020 Sathianathen et al. demonstrated that enzalutamide was the agent with the best OS benefit in this disease space, particularly in patients with low-volume disease.3 Irrespective of the analysis performed, it appears that 2nd generation anti-androgens have superior OS benefits compared to docetaxel and have a more favorable safety profile, particularly with apalutamide.1

The addition of 2nd generation anti-androgens to a standard of care regimen of ADT and docetaxel has shown OS benefits in both PEACE-1 and ARASENS. Conversely, does docetaxel addition to a regimen of ADT and a 2nd generation anti-androgen improve OS? Given the lack of primary evidence evaluating this, Roy et al. recently conducted an updated network meta-analysis following the publication of these two trials evaluating triplet therapy, with 11 total trials included. When compared to the combination of ADT and a 2nd generation anti-androgen, triplet therapy with docetaxel had a nonsignificant OS benefit (HR: 0.89, 95% CI: 0.68-1.16), while ADT plus docetaxel (HR: 1.16, 95% CI: 0.94-143) and ADT alone (HR: 1.46, 95% CI: 1.30-1.64) had inferior OS outcomes. In a Bayesian analysis with results presented using P-score ordering, the triplet was the most effective treatment strategy (P score= 0.936) followed by ADT plus novel hormonal therapy (P score= 0.704).4

Real-world Utilization of Novel Agents

With the emergence of multiple combination treatment strategies in the mHSPC disease space, ADT monotherapy +/- a first generation anti-androgen is no longer standard of care in the first line setting for patients presenting with mHSPC, regardless of tumor burden. As one would expect, however, the uptake of such agents in the real world has been less than ideal, with several studies examining utilization of treatment options for men with mHSPC.

  1. Analysis of an IQVIA claims-based dataset of 17 million cancer patients and 10,000 providers across the United States was presented at AUA 2021. This demonstrated that utilization of 2nd generation anti-androgens in 2021 has remained low at 30% of all eligible mHSPC patients. Utilization of chemotherapy amongst medical oncologists has decreased from 33% of eligible patients in 2016 to 12% in 2021. This analysis also demonstrated that uptake of guidelines-recommend treatment for mHSPC patients has been significantly slower amongst urologists, compared to medical oncologists.
  2. Among 3,556 Canadian men with mHSPC older than 66 years of age, the majority of patients (78.6%) were treated with only a conventional ADT regimen, whereas only 11.2% of men received treatment intensification with docetaxel, and 1.5% received abiraterone acetate + prednisolone. In this study, the median survival amongst the whole population was 18 months (IQR 10-31 months).5
  3. Presented at the ASCO 2022 annual meeting, Freedland and colleagues assessed reasons behind the lack of treatment intensification for men with mHSPC using data from US academic/community practices. In the first-line setting, most patients received ADT ± NSAA alone (69%), while treatment intensification rates with ADT + novel hormonal therapy (26%) or ADT + chemotherapy (4%) were low. Following the initial treatment course, an additional 166 patients (27%) received subsequent treatment intensification while still castration-sensitive, prior to progression to castration resistant disease. 
figure-1-mHSPC-treatment-utilization2x.jpg

The top 5 reasons cited why physicians did not provide their patients with initial novel hormonal therapy were concerns regarding drug tolerability (38%), lack of clinical trial evidence of overall survival improvement (31%), lack of reimbursement (26%), patient financial constraints (20%), and questions about sequencing novel hormonal therapies earlier as compared to later in disease (21%).

  1. Using the Flatiron Health Electronic Health Record database, Swami et al. reported that among men with metastatic newly diagnosed prostate cancer, the majority of patients (54%) received only ADT therapy. Among patients treated with a novel hormonal therapy, an alternate novel hormonal therapy was the most common next therapy and was associated with improved median overall survival over docetaxel: abiraterone followed by docetaxel versus enzalutamide (8.7 versus 15.6 months; adjusted HR 1.32, p = 0.009) and enzalutamide followed by docetaxel versus abiraterone (9.7 versus 13.2 months, adjusted HR 1.40, p = 0.009).6 

Upcoming Trials

There continues to be an influx of trials of novel agents in the mHSPC disease space. The combination of darolutamide and ADT is being evaluated in two studies: ARANOTE and ARASEC. ARANOTE is an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of patients with evidence of mHSPC by conventional imaging. Patients will be randomized in a 2:1 fashion to darolutamide 600 mg twice daily or placebo, plus ADT:

figure-2-mHSPC-treatment-utilization2x.jpg

The primary endpoint is rPFS, with secondary endpoints including OS, time to CPRC, time to initiation of subsequent antineoplastic therapy, time to PSA progression, rates of undetectable PSA, time to pain progression, and safety and adverse events. Accrual started February 2021 with an expected final completion date of March 2024.

ARASEC is a US-based, phase 2, open-label, single-arm study with an external control arm. Patients with mHSPC will receive darolutamide 600 mg twice daily plus ADT. The control arm for ARASEC will be derived from the 393 patients with mHSPC treated with ADT alone in the CHAARTED trial. Patients in the active arm will be matched 1:1 to patients in the control arm using important baseline characteristics such as age, ECOG PS, extent of disease defined as low or high volume according to CHAARTED, and presence of bone and visceral metastases.

figure-3-mHSPC-treatment-utilization2x.jpg

The primary endpoint is PFS, with secondary endpoints of OS, rPFS, time to CPRC, complete PSA response rate at 6 months, and safety. Accrual started November 2021 with an expected final completion date of June 2024.

Following the success of 177Lu-PSMA-617, a high-affinity prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, in the mCRPC space with the VISION7 and TheraP8 trials, attempts have been made to move this drug further forward in the prostate cancer disease spectrum. One such disease space is first line mCSPC. The PSMAddition trial (NCT04720157) is an international, prospective, open label, randomized, phase 3 trial in adults with mHSPC. To be eligible, patients must have PSMA-positive disease (determined by [68Ga]Ga-PSMA-11 PET/CT) and be treatment-naïve or minimally treated candidates for hormonal therapy. A target of approximately 1,126 patients will be randomized in a 1:1 fashion to receive 177Lu-PSMA-617 (7.4 GBq i.v. every 6 weeks, ≤6 cycles) plus standard of care or standard of care alone (control arm). In this context, standard of care is second generation anti-androgen and ADT.

figure-4-mHSPC-treatment-utilization2x.jpg

The primary endpoint is rPFS, as assessed by blinded independent centralized review. Upon centrally confirmed radiographic progression, participants in the control arm can cross over to the 177Lu-PSMA-617 arm. The key secondary endpoint is overall survival, for which final analysis will occur at approximately 384 deaths. The first patient was enrolled on trial on June 9, 2021, and currently 19 countries are participating in North America, Europe, and Asia. The estimated study completion date is December 2025.

Similarly, with the success of poly (ADP-ribose) polymerase (PARP) inhibitors in mCRPC patients with altered homologous recombination repair (HRR)/DNA damage response (DDR) genes, studies have been designed to evaluate the efficacy of these agents in the mHSPC disease space. TALAPRO-3 (NCT04821622) is a phase III, double-blind, randomized trial that will compare the combination of talazoparib plus enzalutamide versus placebo plus enzalutamide in men with mHSPC with DDR/HRR alterations.

figure-5-mHSPC-treatment-utilization2x.jpg

A Phase II study of talazoparib monotherapy (TALAPRO-1) demonstrated robust antitumor activity in men with heavily pretreated, HRR-mutated mCRPC.9 Androgen receptor blockade downregulates HRR gene regulation, which has been hypothesized to induce a “BRCAness” phenotype. PARP inhibition is also expected to increase sensitivity to androgen receptor-directed therapies. Thus, it is hypothesized that the combination of talazoparib and enzalutamide could be synergistic. Approximately 550 patients with mHSPC harboring DDR/HRR alterations will be randomized to talazoparib (0.5 mg once daily) plus enzalutamide (160 mg once daily) or placebo (once daily) plus enzalutamide (160 mg once daily). Patients will have alterations in at least one of 12 DDR/HRR genes known to sensitize to PARP inhibitors (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C). The primary endpoint is rPFS. Secondary endpoints include overall survival, safety, and patient-reported outcomes. Study start date was May 2021 with an estimated primary completion date of December 2024.

The ZZFIRST trial, based in Spain, is a multicenter, open-label, randomized, investigator-initiated phase 2 clinical trial of patients with mHSPC. Patients will begin treatment with enzalutamide 160 mg/day for two 28-day cycles in addition to standard ADT. Following this initial lead-in period, patients are then randomized and stratified based on homologous recombination gene alterations on a 1:2 ratio to either continue enzalutamide 160 mg/day or to receive enzalutamide 160 mg/day plus talazoparib 0.5 mg/day. In both arms, patients will continue ADT throughout the trial. Treatment will continue until progressive disease or unacceptable toxicity.

figure-6-mHSPC-treatment-utilization2x.jpg

The primary study endpoint is PSA-complete response defined as the percentage of patients with PSA < 0.2 ng/mL at 12 months of therapy. Secondary endpoints include PSA response and time to development of castration resistant disease, the correlation between molecular and transcriptomic signatures with antitumor activity, the effect of enzalutamide and ADT on DNA repair function, and the safety and tolerability of the combination treatment approach. This trial was opened to accrual in July 2020 at 9 sites in Spain. As of December 2021, 48 patients have been enrolled and are receiving study treatment of a targeted 54 participants.

Finally, the SAABR trial is a single arm phase II trial that will evaluate abiraterone + atezolizumab + GnRH analog with SBRT in patients with mHSPC. Preclinical studies have shown that SBRT can induce an immunogenic effect through enhanced expression of the PD-L1 protein on tumor and immune cells. Furthermore, outcomes in subjects with locally advanced disease enrolled on STAMPEDE suggest that prostate radiation therapy may be associated with a reduction in treatment failure. Atezolizumab will be administered to men with newly diagnosed mHSPC by IV infusion (1200 mg IV over 60 minutes every 3 weeks) followed after Cycle 1 by abiraterone acetate (1000 mg PO every day with prednisone 5 mg daily), ADT (GnRH analog), and SBRT (7.25-7.50 Gy x 5 fractions to prostate and seminal vesicles every other day starting at Cycle 5 Day 1 ± 5 days) until unacceptable toxicity, protocol defined progression, or 2 years of treatment. Atezolizumab will be continued for a maximum of 2 years. Continuation of abiraterone acetate and ADT beyond 2 years is at the discretion of the treating physician per local standard of care. The study schema for SAABR is as follows:

figure-7-mHSPC-treatment-utilization2x.jpg

The primary objective is failure-free rate at 2 years, with failure defined as biochemical failure, radiographic progression, or death from any cause. Secondary objectives include symptomatic skeletal events defined as a symptomatic fracture (surgery or radiation to the bone or spinal cord compression), prostate cancer specific survival, OS, and safety/tolerability.

Conclusions

Network meta-analyses and real-world observations provide some clarity as to the preferred treatment choice for men with mHSPC. The recent FDA approved triplet therapy of ADT + docetaxel + darolutamide on August 5, 2022, is sure to generate an uptake of real-world evidence in the coming years, but there is concern for a significant portion of patients not receiving any treatment intensification outside of a clinical trial setting. As we move forward into the triplet therapy era, further work understanding a lack of treatment intensification is necessary.


Published: August 2022

Written by: Rashid K. Sayyid, MD, MSc, Zachary Klaassen, MD, MSc, and Christopher J.D. Wallis, MD, PhD
References:
  1. Mori K, Mostafaei H, Motlagh RS, et al. Systemic therapies for metastatic hormone-sensitive prostate cancer: network meta-analysis. BJU Int. 2021;12(4):423-433.
  2. Wang L, Paller CJ, Hong H, et al. Comparison of Systemic Treatments for Metastatic Castration-Sensitive Prostate CancerA Systematic Review and Network Meta-analysis. JAMA Oncol. 2021;7(3):412-420.
  3. Sathianathen NJ, Koschel S, Thangasamy IA, et al. Indirect Comparisons of Efficacy between Combination Approaches in Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis. Eur Urol. 2020;77(3):365-372.
  4. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
  5. Wallis CJD, Malone S, Cagiannos I, et al. Real-World Use of Androgen-Deprivation Therapy: Intensification Among Older Canadian Men With de Novo Metastatic Prostate Cancer. JNCI Cancer Spectr. 2021;5(6):pkab082.
  6. Swami U, Sinnott JA, Haaland B, et al. Treatment Pattern and Outcomes with Systemic Therapy in Men with Metastatic Prostate Cancer in the Real-World Patients in the United States. Cancers (Basel). 2021;13(19):4951.
  7. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385:1091-1103.
  8. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
  9. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): An open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264.

The Current Landscape of Metastatic Hormone Sensitive Prostate Cancer: Impact of Disease Volume and Timing of Metastases

Introduction

Since 2015, the metastatic hormone sensitive prostate cancer (mHSPC) disease space now has several options of doublet and triplet therapy, using ADT as the backbone of treatment, leading to an overall survival (OS) advantage versus ADT alone. Thus, this has changed the standard of care for treatment intensification for these men. The incidence of metastatic prostate cancer at diagnosis ranges from ~5-50%, with vast geographic differences. Such patients are defined as having de novo or synchronous mHSPC. Additionally, some men who are initially diagnosed with non-metastatic disease will have progression to metastasis prior to development of castration resistance, also known as metachronous mHSPC.1

This distinction between synchronous and metachronous mHSPC is of utmost clinical importance given differences in prognosis,2 genomic mutational profiles,3,4 and recommended systemic treatment options between these two groups.3 Both groups can be further stratified by volume of metastatic disease, most commonly by using the CHAARTED high-volume criteria as follows: presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.5 As such four distinct subgroups become clinically relevant (median OS per CHAARTED and GETUG-15 among men receiving ADT alone, ie. the control groups in these trials):

  1. Metachronous and low volume: ~8 years
  2. Metachronous and high volume: 4.5 years
  3. Synchronous and low volume: 4.5 years
  4. Synchronous and high volume: 3 years

Given that the results of the key phase 3 mHSPC randomized clinical trials in the intention to treat population are discussed in another Center of Excellence article, the following article will take on more a nuanced approach assessing outcomes of these trials focusing specifically on timing of metastatic disease (de novo versus metachronous) and volume of disease (high versus low). Additionally, we will address several specific treatment considerations (ie. metastasis directed therapy [MDT] and prostate radiotherapy) for those with very low, or oligometastatic, mHSPC.

ADT + Docetaxel

The CHAARTED trial was initially published in 2015 and an updated analysis was published in 2018 evaluating the survival benefit of docetaxel addition to ADT by volume status.6 This trial was enriched for high volume disease (64.9% of total cohort) and 72.8% of patients presented with de novo disease. This updated analysis demonstrated that the benefit of docetaxel addition is restricted to patients with high volume disease (median OS 51.2 months for docetaxel + ADT versus 34.4 months for ADT alone; HR 0.63, 95% CI 0.50 to 0.79) but not low volume disease (median OS 63.5 months for docetaxel + ADT versus not reached for ADT alone; HR: 1.04, 95% CI 0.70 to 1.55):

figure-1-mHSPC-volume-timing2x.jpg

Patients with high volume disease appeared to derive a benefit from docetaxel addition irrespective of whether they present with de novo metastatic disease (median OS 48.0 versus 33.1 months; HR 0.63, 95% CI 0.59 to 0.81) or metastatic recurrence following prior local therapy (median OS 66.9 versus 51.7 months; HR 0.72, 95% CI 0.36 to 1.46). There was no benefit seen in the low volume groups, irrespective of whether presenting with de novo or recurrent mHSPC.6 The most recent update at ASCO 2022 presented the 8-year OS data for patients from the CHAARTED trial. This update confirmed an OS benefit for docetaxel addition in the high-volume cohort, however, it also demonstrated a mortality benefit for synchronous low-volume mHSPC patients with OS rates of 44.6% versus 40.9% (HR 0.77, 95% CI 0.51 to 1.18), but not metachronous low-volume patients (43.4% versus 64.2%; HR 1.65, 95% CI 0.95 to 2.87):

figure-2-mHSPC-volume-timing2x.jpg

The GETUG-15 trial included 70.6% patients with de novo mHSPC, with only 50% of patients considered high volume per the CHAARTED criteria (compared to 64.9% in CHAARTED). This may in part explain the negative OS outcome seen in GETUG-15. Long-term follow-up from GETUG7 and combined analysis from GETUG-15 and CHAARTED8 demonstrated benefit for docetaxel addition in the high volume mHSPC, but not those with low-volume disease.

Updated results from the STAMPEDE trial published in 2019 with a median follow up of 78.2 months retrospectively evaluated imaging results for patients with available baseline staging scans (76%). This demonstrated consistent OS benefits for docetaxel in both the low and high-volume cohorts (CHAARTED criteria). In low volume patients, median OS improved from 76.7 months to 93.2 months with docetaxel (HR 0.76, 95% CI 0.54 to 1.07) compared to 39.9 months from 35.2 months in the high-volume patients (HR 0.81, 95% CI 0.64 to 1.02) (interaction by metastatic burden p=0.827).9

figure-3-mHSPC-volume-timing2x.jpg

At ASCO 2022, the results of a STOPCAP M1 collaborative meta-analysis of individual patient data from GETUG-15, STAMPEDE, and CHAARTED was presented. This meta-analysis included all 2,261 randomized patients, with median follow-up of 6 years. There were clear benefits for docetaxel on OS (HR 0.79, 95% CI 0.70 to 0.88), progression-free survival (PFS) (HR 0.70, 95% CI 0.63 to 0.77) and failure-free survival (FFS) (HR 0.64, 95% CI 0.58 to 0.71) in the overall pooled cohort. With evidence of non-proportional hazards, the estimated 5-year absolute differences were: OS 11% (95% CI 6 to 15%), PFS 9% (95% CI 5 to 13%) and FFS 9% (95% CI 6 to 12%).

Notably, the relative effect of docetaxel on PFS differed by volume of metastases (interaction p=0.027; high volume HR 0.60, 95% CI 0.52 to 0.68; low volume HR 0.78, 95% CI 0.64 to 0.94) and timing of metastatic disease (interaction p=0.077; synchronous HR 0.67, 95% CI 0.60 to 0.75; metachronous HR 0.89, 95% CI 0.67 to 1.18). OS results were similar. When metastatic disease volume and timing were combined, docetaxel appeared to improve PFS and OS for all men, except those with low volume, metachronous disease, though there is a clear dose-response relationship with a diminishing benefit to docetaxel chemotherapy from high-volume synchronous disease, to high-volume metachronous disease, to low-volume synchronous disease, and finally to low-volume, metachronous disease:

figure-4-mHSPC-volume-timing2x.jpg

Taken together, it appears that docetaxel addition has a clear OS benefit in patients with high volume disease, irrespective of timing of disease (synchronous or metachronous). Patients with synchronous low-volume disease may have a modest benefit with docetaxel addition though those with low volume, metachronous (i.e. recurrent) mHSPC do not benefit from docetaxel addition to ADT.

ADT + Abiraterone/Prednisone

The LATITUDE trial published in 2017 included only patients with de novo, high risk prostate cancer, leading to the LATITUDE high risk criteria (as opposed to high versus low volume), defined as patients with two or more of the following characteristics: (i) Gleason Score ≥8, (ii) presence of ≥3 lesions on bone scan, and (iii) presence of measurable visceral lesions. These risk criteria were applied in a post hoc subgroup analysis of the 2017 STAMPEDE “abiraterone comparison”.10

Among 990 patients, 901 patients with available data were included. LATITUDE high-risk disease was present in 52% while the remainder had so-called low-risk disease. Overall survival benefits with ADT + abiraterone/prednisone addition were seen in both the low (HR 0.66, 95% CI 0.44 to 0.98) and high-risk groups (HR 0.54, 95% CI 0.41 to 0.70). The heterogeneity of treatment effect between high- and low-risk groups was not statistically significant (p-interaction = 0.39). When the CHAARTED criteria were applied in this same cohort, consistent OS benefits were again seen in both the low- (HR 0.64, 95% CI 0.42 to 0.97) and high-volume groups (HR 0.60, 95% CI 0.46 to 0.78).

ADT + Apalutamide vs ADT

In the TITAN trial, 81% of patients presented with de novo mHSPC and 62.7% of patients had CHAARTED high volume disease.11 A subgroup analysis from TITAN demonstrated that addition of apalutamide maintained OS benefits irrespective of:

Disease volume
  • High: HR: 0.70 (95% CI: 0.56-0.88)
  • Low: HR: 0.52 (95% CI: 0.35-0.79)
Synchronous versus metachronous presentation
  • Synchronous: HR: 0.68 (95% CI: 0.55-0.85)
  • Metachronous: HR: 0.39 (95% CI: 0.22-0.69)

ADT + Enzalutamide vs ADT

In 2021, Sweeney et al. performed subgroup analyses of patients with metachronous mHSPC treated in the ENZAMET trial of enzalutamide. Of the 1,125 enrolled patients, 312 (28%) had known metachronous disease and 205 (66%) had low-volume disease at entry. For the metachronous mHSPC group overall, OS HR was 0.56 (95% CI 0.29 to 1.06) for enzalutamide addition. Interestingly, this OS benefit seemed to be driven mainly by benefits in the low-volume subgroup (HR 0.40, 95% CI 0.16 to 0.97) with no apparent benefit in the high volume metachronous subgroup (HR 0.86, 95% CI 0.33 to 2.22). These results may have been secondary to the high use of concurrent docetaxel in the high-volume subgroup (60% vs 15% in patients with low-volume disease), which may have diluted an OS benefit in the high volume subgroup.12

Most recently at ASCO 2022, Dr. Ian Davis presented the most recent update of the ENZAMET trial. With regards to subgroup analyses, enzalutamide demonstrated consistent OS benefits across the following strata:

Planned early docetaxel (p-value for interaction=0.09)
  • Yes: HR 0.82 (95% CI 0.63 to 1.06)
  • No: HR 0.60 (95% CI 0.47 to 0.78)
Volume of disease (p-value for interaction=0.06)
  • Low: HR 0.54 (95% CI 0.39 to 0.74)
  • High: HR 0.79 (95% CI 0.63 to 0.98)
Timing of presentation (p-value for interaction=0.91)
  • Synchronous: HR 0.70 (95% CI 0.56 to 0.87)
  • Metachronous: HR 0.71 (95% CI 0.52 to 0.98)
While no significant interaction was demonstrated, there are clear differences in the relative benefit between groups based on planned early use of docetaxel. Thus, we must consider which patients benefited from treatment intensification with both docetaxel and enzalutamide (triplet therapy). It appears that the subgroup with synchronous, high-volume mHSPC were the only ones to benefit from such a regimen with the Kaplan Meier curves below demonstrating early separation of the enzalutamide/docetaxel arm from the remaining ones (enzalutamide, NSAA, NSAA + docetaxel):

figure-5-mHSPC-volume-timing2x.jpg

In the ARCHES trial, patients with predominately high-volume (63%) and de novo (66.7%) disease were randomized to enzalutamide + ADT or ADT alone. Notably, 17% of the cohort had previously received docetaxel.13 The most recent update of the trial was presented at ASCO GU 2022, noting that there were consistent benefits for the use of enzalutamide in addition to ADT in all disease volume and M0/M1 populations:

  • Synchronous, high volume: HR 0.63 (95% CI 0.48 to 0.81)
  • Synchronous, low volume: HR 0.65 (95% CI 0.39 to 1.08)
  • Metachronous, high volume: HR 0.77 (95% CI 0.39 to 1.50)
  • Metachronous, low volume: HR 0.63 (95% CI: 0.26 to 1.54)

ADT + Docetaxel + Abiraterone

Initially presented at ASCO 2021 and subsequently published in the Lancet in 2022,22 the PEACE-1 trial employed a 2x2 design to assess, (separately and combined) the impact of the addition of abiraterone + prednisone + ADT and radiation therapy to standard of care therapy in men with de novo mHSPC. Among patients with high volume disease, the addition of abiraterone + prednisone + ADT to standard of care resulted in a 53% improvement in rPFS with median rPFS of 1.6 years on the standard of care arm and 4.1 years on the standard of care plus abiraterone + prednisone + ADT arm (HR 0.47, 95% CI 0.36 to 0.60). The addition of abiraterone + prednisone + ADT to standard of care in patients with low volume disease resulted in a 42% improvement in rPFS with median rPFS of 2.7 years on the standard of care arm versus not yet reached on the standard of care plus abiraterone + prednisone + ADT arm (HR 0.58, 95% CI 0.39-0.87). With regards to OS, this effect was seen across subgroups, including those with high volume disease (HR 0.72, 95% CI 0.55 to 0.95) and low volume disease (HR 0.83, 95% CI 0.50 to 1.38; interaction P-value 0.64). Notably, the OS data is immature for the low volume patients due to a small number of events.

ADT + Docetaxel + Darolutamide

The ARASENS trial evaluating addition of darolutamide to standard of care therapy consisting of ADT + docetaxel was presented at ASCO GU 2022 and concurrently published in The New England Journal of Medicine.14 Metastatic burden classification by CHAARTED criteria was not available in this trial, however disease stratification by TNM metastatic burden (M1b versus M1c) demonstrated consistent benefits for darolutamide addition to ADT and docetaxel. In the M1b subgroup (with bony metastases), HR for OS was 0.66 (95% CI 0.54 to 0.80). In the M1c group (with visceral metastases), HR for OS was 0.76 (95% CI 0.53 to 1.10), with median OS of 49.0 months in the darolutamide arm and 42.0 months in the placebo arm.

The following table summarizes OS outcomes by CHAARTED disease volume criteria and presentation (synchronous vs metachronous) among men with mHSPC:
table-1-mHSPC-volume-timing2x.jpg

Specific Considerations for Low Volume mHSPC Patients

Beyond systemic treatment intensification, there is a role for therapy targeting either the primary (for patients with de novo disease) or metastatic sites in certain patient groups.

Prostate radiotherapy: STAMPEDE (Arm H) was an open label, randomized controlled phase III trial of 2,061 men with de novo mHSPC randomized to standard of care + radiotherapy or standard of care. Subgroup analysis by metastatic volume (CHAARTED criteria) was planned a priori. Radiotherapy when stratified by metastatic burden showed an OS benefit in the low volume group (HR 0.68, 95% CI 0.52 to 0.90) with restricted mean survival time improved by 3.6 months from 45.4 to 49.1.15 Updated results of this trial were published June 2022 in PLoS Medicine.16 With a median follow up of 61.3 months, prostate radiotherapy continued to demonstrate OS benefits in patients with low metastatic burden (HR 0.64, 95% CI 0.52 to 0.79). No benefit was seen in patients with high metastatic burden (HR 1.11, 95% CI 0.96 to 1.28; interaction p=0.001).

HORRAD was a multicenter trial of 432 patients with previously untreated, de novo mHSPC men randomized in a 1:1 fashion to either ADT with external beam radiotherapy or ADT alone. No subgroup analyses by CHAARTED volume criteria was performed, but subgroup analysis by number of metastatic lesions suggested potential (albeit not statistically significant) OS benefit for radiotherapy in patients with <5 metastatic sites (HR 0.68, 95% CI 0.42 to 1.10).17

In 2019, a systematic review and meta-analysis of the STAMPEDE Arm H and HORRAD trials was performed by the STOPCAP collaboration. Pooled results of 2,126 men demonstrated no overall OS improvement (HR 0.92, 95% CI 0.81 to 1.04) or PFS (HR 0.94, 95% CI to 0.84-1.05). However, the effect of prostate radiotherapy on OS varied by metastatic burden (<5 versus ≥5 bone metastases: interaction HR 1.47, 95% CI 1.11 to 1.94, p=0.007). Furthermore, there was a 7% improvement in 3-yr survival in men with fewer than five bone metastases.18

Metastasis-Directed Therapy: In addition to systemic treatment intensification and local prostate-directed radiotherapy, treatment may be intensified by targeting local treatment to sites of metastatic disease. To date, there is no level one evidence supporting MDT in synchronous oligometastatic mHSPC disease space. Three randomized trials to date have evaluated MDT (stereotactic body radiotherapy or surgical metastasectomy) in patients with metachronous, oligometastatic mHSPC.

The STOMP trial was a multicenter, randomized phase II trial that prospectively evaluated the effects of MDT for patients with evidence of oligometastatic disease on choline PET/CT (up to three extracranial sites) who had received prior treatment with curative intent and had evidence of biochemical recurrence with testosterone >50 ng/ml (i.e. metachronous, oligometastatic mHSPC). Between 2012 and 2015, 62 patients were randomized 1:1 and MDT was either SBRT or metastasectomy. The primary endpoint was time to initiation of ADT (called ADT-free survival). ADT was initiated for symptoms, progression beyond three metastases, or local progression of known metastatic disease. Time to castration resistance was a secondary endpoint (called CRPC-free survival). The updated five-year results were presented at GU ASCO 2020. With a median follow up of 5.3 years, the five-year ADT-free survival was 8% in the surveillance arm compared to 34% for the MDT group (HR 0.57, 95% CI 0.38 to 0.84, log-rank p=0.06). No differences were seen between groups when stratified by nodal versus non-nodal metastases. Secondary endpoint of CRPC-free survival at 5 years was 53% in subjects under surveillance and 76% in those receiving MDT (HR 0.62, 80% CI 0.35 to 1.09).19

The ORIOLE trial was a randomized phase II trial of 54 men with metachronous, oligometastatic mHSPC (up to three sites). Metastatic sites were diagnosed via 18F-DCFPyL PET/CT. Between 2016 and 2018, patients were randomized in a 2:1 fashion to receive SABR or observation. The primary outcome was progression at 6 months, defined as serum PSA increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Progression at six months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (p = 0.005). Treatment with SABR improved median PFS (not reached vs 5.8 months; HR 0.30, 95% CI 0.11 to 0.81). No toxic effects of grade 3 or greater were observed.20

SABR-COMET was a randomized, open-label phase II study of patients with oligometastatic disease (up to five sites) between February 2012 and August 2016. This trial was not restricted to patients with prostate cancer and also included lung, breast, and colorectal cancer patients. Of the 99 patients in this trial, 18 (18%) had prostate cancer. After stratifying by the number of metastases (1–3 vs 4–5), patients were randomized in a 1:2 fashion to receive either palliative standard of care alone or standard of care plus SABR. In an updated analysis published in 2020 (median follow up 51 months), the five-year OS rate was 17.7% (95% CI 6-34%) in the control arm and 42.3% in the SABR arm (95% CI 28-56%, stratified log-rank p=0.006). The corresponding median OS was 28 months and 50 months, respectively. There were no new grade 2-5 adverse events and no differences in QOL between the arms.21,22

Synthesizing the Timing of Metastasis and Volume of Disease Relationship

In clinical practice, the two faces of mHSPC may be very different. Dr. Chris Sweeney has lectured at length regarding the differences between de novo mHSPC (ie. a 55-year-old with no comorbidities and high volume de novo/synchronous metastatic disease) and metachronous mHSPC (ie. an 82-year-old with congestive heart failure and coronary artery disease with 2 bone metastases 10 years after prostatectomy). As highlighted above, when assessing the 8-year OS CHAARTED data, the addition of docetaxel to ADT shows a clear survival benefit for those with de novo high volume disease and those with metachronous high volume disease, a modest effect for those with synchronous low volume disease, and no benefit for those with metachronous low volume disease, men with biochemical relapse, and in the adjuvant setting. Alternatively, this is not the case for second generation anti-androgens: enzalutamide + ADT in ENZAMET showed improved PFS and OS among all subgroups (synchronous high-volume, synchronous low-volume, metachronous high-volume, and metachronous low-volume). This is also true in the ARCHES, TITAN, LATITUDE and STAMPEDE-abiraterone trials. Interestingly, subgroup analyses from ENZAMET (which permitted docetaxel use), demonstrate that docetaxel addition to enzalutamide + ADT only shows a survival benefit in the poorest prognosis group of men with synchronous, high volume disease; these findings are similar to those reported PEACE-1 and ARASENS. As such, it is important when developing a mHSPC treatment plan to consider the presentation and distribution of metastases, and the available options for ADT + a second/third agent:

figure-6-mHSPC-volume-timing2x.jpg

Published: August 2022

Written by: Christopher J.D. Wallis, MD, PhD, Rashid K. Sayyid, MD, MSc, and Zachary Klaassen, MD, MSc
References:
  1. Cancer Stat Facts: Prostate Cancer. National Cancer Institute. Available at  https://seer.cancer.gov/statfacts/html/prost.html. Accessed: July 17, 2022.
  2. Weiner AB, Siebert AL, Fenton SE, et al. First-line Systemic Treatment of Recurrent Prostate Cancer After Primary or Salvage Local Therapy: A Systematic Review of the Literature. Eur Urol Oncol. 2022.
  3. Deek MP, Van der Eecken K, Phillips R, et al. The mutational landscape of metastatic castration-sensitive prostate cancer: the spectrum theory revisited. Eur Urol. 2021;80:632-640
  4. Stopsack KH, Nandakumar S, Wimber AG, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26:3230-3238.
  5. Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N ENgl J Med. 2015;373:737-746.
  6. Kyriakopoulos CE, Chen YH, Carducci MA, 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(11):1080-1087.
  7. Marino P, Sfumato P, Joly F, et al. Q-TWiST analysis of patients with metastatic castrate naive prostate cancer treated by androgen deprivation therapy with or without docetaxel in the randomised phase III GETUG-AFU 15 trial. Eur J Cancer. 2017;84:27-33.
  8. Gravis G, Boher J, Chen Y, et al. Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies. Eur Urol. 2018;73(6):847-855.
  9. Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019;30(12):1992-2003.
  10. Hoyle AP, Ali A, James ND, et al. Abiraterone in “High-” and “Low-risk” Metastatic Hormone-sensitive Prostate Cancer. Eur Urol. 2018;76(6):719-728.
  11. Chi KN, 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. J Clin Oncol. 2021;39(2):2294-2303.
  12. Sweeney CJ, Martin AJ, Stockler MR, et al. Overall survival of men with metachronous metastatic hormone-sensitive prostate cancer treated with enzalutamide and androgen deprivation therapy. Eur Urol. 2021;80:275-279.
  13. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37(32):2974-2986.
  14. Chi KN, 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. J Clin Oncol. 2021;39(2):2294-2303.
  15. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
  16. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Medicine. 2022;19(6):e1003998.
  17. Boeve LMS, Hulshof MCCM, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
  18. Burdett S, Boeve LM, Ingleby FC, et al. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol. 2019;76(1):115-124.
  19. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36(5):446-453.
  20. Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate CancerThe ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650-659.
  21. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058.
  22. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-2838.

The Current Landscape of Metastatic Hormone Sensitive Prostate Cancer: A Plethora of Treatment Options

Introduction

The treatment landscape of metastatic hormone sensitive prostate cancer (mHSPC) has evolved rapidly since the introduction of combination chemohormonal therapy with docetaxel and androgen deprivation therapy (ADT) in 2015.1 This includes a variety of treatment intensification strategies including both systemic therapy and local, prostate-directed radiotherapy. In addition to docetaxel, there are several U.S. Food and Drug Administration (FDA) approved agents in this disease space in combination with ADT:
Written by: Zachary Klaassen, MD, MSc, Rashid K. Sayyid, MD, MSc, and Christopher J.D. Wallis, MD, PhD
References:
  1. Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N ENgl J Med. 2015;373:737-746.
  2. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(2):149-158.
  3. Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N ENgl J Med. 2015;373:737-746.
  4. James ND, Sydes MR, Clarke NW, 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. Lancet. 2016;387(10024):1163-1177.
  5. Tucci M, Bertaglia V, Vignani F, et al. Addition of Docetaxel to Androgen Deprivation Therapy for Patients with Hormone-sensitive Metastatic Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016;69(4):563-573.
  6. Kyriakopoulos CE, Chen YH, Carducci MA, 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(11):1080-1087.
  7. Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019;30(12):1992-2003.
  8. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New Engl J Med.. 2017;377(4):352-360.
  9. Hoyle AP, Ali A, James ND, et al. Abiraterone in “High-” and “Low-risk” Metastatic Hormone-sensitive Prostate Cancer. Eur Urol. 2018;76(6):719-728.
  10. James N, Clarke NW, Cook A, et al. Abirtaterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year followup results from the STAMPEDE randomized trial. Int J Cancer. 2022;151(3):422-434.
  11. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
  12. Chi KN, 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. J Clin Oncol. 2021;39(2):2294-2303.
  13. Agarwal N, McQuarrie K, Bjartell A, et al. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019;20(11):1518-1530.
  14. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381(2):121-131.
  15. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37(32):2974-2986.
  16. Fizai K, Foulon S, Carles J, 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(10336):1695-1707.
  17. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-1142.
  18. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
  19. Boeve LMS, Hulshof MCCM, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
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