Since 2015, multiple combination treatment strategies have emerged for the management of patients with metastatic hormone sensitive prostate cancer (mHSPC). The addition of docetaxel and/or androgen receptor-axis targeted (ARAT) agents to standard androgen deprivation therapy (ADT), in the form of doublet and triplet treatment strategies, has demonstrated overall survival benefits in this cohort of patients. As such, these drug combinations have changed the standard of care approaches in these men.1
The incidence of metastatic prostate cancer at diagnosis ranges from ~5-50%, with significant geographic differences as previously described.2 Such patients are defined as having de novo or synchronous mHSPC. Additionally, there exits a subset of men initially diagnosed with non-metastatic disease, many of whom have received prior definitive local treatment, who will have progression to a metastatic state prior to development of castration resistance. This is known as metachronous mHSPC. This distinction between synchronous (i.e. de novo) and metachronous presentations is of utmost clinical importance given the known differences in underlying genomic mutational profiles and prognoses, influencing the subsequent choice of treatment intensification.3,4 These two cohorts can be further subdivided based on the volume of metastatic disease at presentation: low and high volumes. The CHAARTED high-volume criteria have been widely adopted in clinical practice, with high volume patients defined 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 overall survival per CHAARTED and GETUG-15 among men receiving ADT alone, ie. the control groups in these trials):
- Synchronous and high volume: 3 years
- Synchronous and low volume: 4.5 year
- Metachronous and high volume: 4.5 years
- Metachronous and low volume: ~8 years
In this Center of Excellence reviewarticle, we presentIndex Patient 1: Synchronous High Volume mHSPC
Index Patient 1: Synchronous High Volume mHSPC
Case Presentation: A 57-year-old previously healthy male with an excellent performance status presents to his primary care physician with complaints of intermittent right hip pain for the last three months. Screening blood work in the form of a complete blood count (CBC) and a comprehensive metabolic panel (CMP) demonstrates elevated liver function tests. A computed tomography scan of the abdomen and pelvis (CT A/P) demonstrates evidence of two bony lesions in the right femur and iliac bone, multiple liver lesions, pelvic nodal enlargement bilaterally, and an enlarged, heterogenous prostate gland. A serum prostate-specific antigen (PSA) test was drawn and demonstrated to be 306.2 ng/ml. A bone scan was obtained and demonstrated no additional lesions. A subsequent CT chest demonstrated small, non-specific lesions in the lower lobes bilaterally. Gleason Score 9 (4+5) prostate cancer was diagnosed in 9/12 cores, confirming synchronous, high volume mHSPC disease.Triplet Therapy
Based on the results from PEACE-1 and ARASENS, as well as subgroup analysis from ENZAMET, it appears that this patient cohort, particularly those who are chemotherapy-fit such as this patient, are most likely to benefit from triplet therapy with docetaxel + an ARAT + ADT.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 +/- radiation therapy to standard of care therapy in men with de novo mHSPC. Among patients with high volume disease, the addition of abiraterone + prednisone to standard of care resulted in a 53% improvement in radiographic progression-free survival (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 arm (HR: 0.47, 95% CI: 0.36 to 0.60). The addition of abiraterone + prednisone to standard of care in patients with low volume disease still 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 overall survival in patients with a de novo presentation, a benefit was seen mainly in those with high-volume disease (median overall survival 5.14 versus 3.57 years; HR 0.77, 95% CI 0.62 to 0.96), with a marginal, non-significant improvement in those low volume de novo disease (median overall survival not reached; HR 0.93, 95% CI 0.69 to 1.28). The OS data is immature for the low volume patients due to a small number of events.
Notably, 81% of patients in the ADT plus docetaxel standard of care control arm subsequently received a next generation hormonal therapy at the time of disease progression. This suggests that early intensification with the addition of abiraterone + prednisone to standard of care therapy results in improvement in rPFS and OS compared to sequential therapy:6
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. 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 bone metastases), HR for overall survival 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:
When stratified by alkaline phosphatase levels, consistent overall survival benefits were seen both in patients with an alkaline phosphatase level above or equal to the upper limit of normal (median overall survival: 49.0 versus 42.0 months; HR: 0.76, 95% CI: 0.56 to 0.85) and a level below the upper limit of normal (median overall survival: 69.0 versus 60.6 months; HR: 0.64, 95% CI: 0.52 to 0.79):7
ADT + Enzalutamide vs ADT
While the ENZAMET trial was designed to compare the combination of ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen, the study design allowed for previous/concurrent use of docetaxel. In this trial, six cycles of docetaxel were given to 65% of patients in the enzalutamide group versus 76% in the standard of care group. As such, it may be argued that results from this study served as the first indication for the benefits of triplet therapy in this disease space.8 An overall survival benefit for enzalutamide addition (versus a nonsteroidal anti-androgen) was seen irrespective of planned early docetaxel use, volume of disease, or timing of presentation:
- 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)
Results from these three trials provide strong evidence to support the use of a triple regimen approach in patients with synchronous, high volume mHSPC. It bears note, however, that routine use of docetaxel may not be feasible in patients with contraindications to taxane therapy, including poor performance status, blood dyscrasias, and peripheral neuropathy. Such patients would likely benefit from ARAT addition to standard ADT:
Written by:
- Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, Ontario
- Christopher J.D. Wallis, MD, PhD, Mount Sinai Hospital and University Health Network, Toronto, Ontario
- Zachary Klaassen, MD, MSc, Medical College of Georgia,Augusta, Georgia, USA