mHSPC

Introduction

Classical theories of metastasis have followed ‘the seed and soil’ hypothesis, the Halstedian model, which proposes an orderly spread of disease from local to distant sites, with the presumption that cancer is an inherently systemic process even in the earliest cases. More contemporary spectrum theories now suggest that the propensity for distant spread exists along a ‘metastatic continuum’. Tumors with limited metastatic potential (i.e., oligometastases) represent a unique subset along this spectrum that could be potentially cured with local ablative therapy (i.e., metastasis-directed therapy [MDT]). This concept is not unique to prostate cancer and has been evaluated in other disease sites including non-small cell lung, colorectal, esophageal, and breast cancers.¹

The majority of the evidence for MDT in the prostate cancer space, to date, has been for patients with recurrent, oligometastatic hormone sensitive prostate cancer. MDT has been evaluated both in lieu of, to avoid/delay the use of systemic therapy, and in combination with systemic therapy to potentially improve efficacy outcomes. In this Center of Excellence article, we discuss the evidence and practical applications for MDT in the recurrent oligometastatic hormone sensitive setting.

Trials of MDT versus Observation/Surveillance for Recurrent Oligometastatic Prostate Cancer

To date, three prospective phase II trials have compared MDT to observation for patients with recurrent oligometastatic hormone sensitive prostate cancer.

The STOMP trial was a multicenter, randomized phase II trial that prospectively evaluated the effects of MDT for eugonadal men 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. Between 2012 and 2015, 62 patients were randomized 1:1 to either surveillance or MDT, consisting of stereotactic body radiotherapy (SBRT) or metastasectomy. The primary endpoint was time to initiation of ADT (i.e., ADT-free survival). ADT was initiated for symptoms, progression beyond three metastases, or local progression of known metastatic disease

After 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: 0.38–0.84, log-rank p = 0.06). No differences were seen between groups when stratified by nodal versus non-nodal metastases:

The secondary endpoint of 5-year CRPC-free survival was 53% in subjects under surveillance and 76% in those receiving MDT (HR 0.62, 80% CI: 0.35-1.09):² 

The ORIOLE trial was a randomized phase II trial of men with recurrent oligometastatic hormone-sensitive prostate cancer (up to three sites). Between 2016 and 2018, 80 men were screened, of which 54 men had 1 to 3 metastases detectable by conventional imaging and had not received ADT within 6 months of enrollment or 3 or more years total. These 54 men were randomized in a 2:1 fashion to receive SBRT or observation. The primary outcome was disease progression at 6 months, defined by a serum PSA increase, radiographic progression on conventional imaging, symptomatic progression, ADT initiation for any reason, or death. 

After a median follow-up of 19 months, disease progression at six months occurred in 19% of patients in the SBRT arm versus 61% of patients in the observation arm (p = 0.005). Patients in the SBRT treatment arm had superior median progression-free survival rates (median: not reached versus 5.8 months; HR: 0.30; 95% CI: 0.11–0.81; p = 0.002):

Secondary to the blinding of the investigative team to the PSMA-targeted PET data during treatment planning, 16 of 36 men treated with SBRT had baseline PET-avid lesions that were not included in the treatment fields. The proportion of men with no untreated lesions with progression at 6 months was 1 of 19 (5%) compared with 6 of 16 (38%) for those with any untreated lesions (p = 0.03). The median progression free survival was unreached among men with no untreated lesions vs 11.8 months among participants with any untreated lesions (HR, 0.26; 95% CI, 0.09-0.76; p = 0.006):³

As such, this was among the first data to suggest the importance of treating all PSMA PET-visible lesions for maximal oncologic benefit in the oligometastatic mHSPC space. 

In 2022, pooled data from the ORIOLE and STOMP trials demonstrated that MDT improves progression free survival from 5.9 months to 11.9 months (HR: 0.44, p<0.001), however without any significant improvements seen in radiographic progression-free survival, time to castration-resistant disease, or overall survival:⁴

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 (18.2%) had prostate cancer. After stratifying by the number of metastases (1–3 versus 4–5), patients were randomized in a 1:2 fashion to receive either palliative standard of care alone or standard of care plus SBRT. 

At a median follow-up of 5.7 years, the primary outcome of overall survival was superior for SBRT-treated patients. The 8-year overall survival rates were 27% and 14% in the intervention and control arms, respectively (HR: 0.50, 95% CI: 0.30–0.84, p = 0.008). The 8-year progression-free survival estimates were 21% and 0%, respectively (HR: 0.45, 95% CI: 0.28–0.72, p < 0.001):

The rates of grade ≥2 acute or late toxic effects were 30% versus 9% (p = 0.019), and the FACT-G quality of life scores declined over time in both arms, but with no differences in quality-of-life scores between the study arms.⁵ 

Combination of MDT + Systemic Therapy for Recurrent Oligometastatic Prostate Cancer

The EXTEND trial was a single center, phase II randomized controlled trial of 87 oligorecurrent men, mostly with mHSPC (>90%), who were randomized 1:1 to intermittent hormone therapy +/- MDT (definitive radiation therapy to all sites of disease). All patients had ≤5 metastases, as defined by conventional imaging (75%) or fluciclovine PET/CT (25%). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. At a median follow-up of 22 months, progression free survival was improved in the combined therapy arm (HR: 0.25, 95% CI: 0.12 – 0.55, p < 0.001). Significantly, ‘eugonadal’ progression free survival was also improved with this combination approach (HR: 0.32, p = 0.03):⁶

SATURN is a phase II trial of 28 men with oligorecurrent extra-pelvic metastases on PSMA-PET/CT following initial treatment with radical prostatectomy. Patients were treated with 6 months of ‘androgen annihilation therapy’, defined as leuprolide + abiraterone acetate/prednisone + apalutamide. After the 1^st month of this systemic therapy, patients received SBRT to all metastases with or without radiotherapy directed to the prostate bed and pelvic lymph nodes. Results of the primary endpoint, the percentage of patients who maintained PSA <0.05 ng/mL six months after testosterone recovery to ≥150 ng/dL, were presented at ASCO GU 2024. Overall, 50% of patients maintained a PSA <0.05 ng/mL six months after testosterone recovery. After a median follow-up of 20 months, the median progression free survival was 19.3 months. Moreover, 81% of patients recovered eugonadal testosterone levels, at a median of 9.4 months from the start of systemic therapy, and the median eugonadal progression free survival was 11.4 months. Grade 3 adverse events related to androgen therapy were observed in 21% of patients, and SBRT had 7.7% grade 2 and no grade 3 toxicity.⁹

There are several important ongoing trials combining systemic therapy with the site specific control offered by MDT. The ADOPT trial is an ongoing phase III trial that is randomizing 280 patients with evidence of recurrent oligometastatic disease (≤4 lesions) on PSMA-PET/CT 1:1 to either MDT (radiotherapy) alone or MDT + 6 months of ADT. The primary endpoint of this trial is 30 month metastases progression free survival, with key secondary endpoints including overall survival, adverse events, and quality of life outcomes:⁷

NRG GU011 (PROMETHEAN) is a randomized phase II trial of SBRT with or without relugolix for early PET-detected recurrent oligometastatic prostate cancer. Eligible patients are those with biochemical recurrence following prior curative intent radiation or surgery for localized prostate cancer, PSA < 10 ng/mL, negative conventional imaging, and 1–5 PET-visible metastases (≥1 extra-pelvic). The primary endpoint is conventional imaging-based radiographic progression free survival. Key secondary endpoints include PET-based radiographic progression free survival, overall survival, and quality-of-life outcome measures:

The VA STARPORT study is a phase II/III randomized trial that evaluates the value of adding PET-directed local therapy to standard systemic therapy for biochemically recurrent patients with evidence of ≤5 metastatic lesions on PSMA-PET/CT. PET-directed local therapy is defined as surgery or radiation to all visible metastases and any prostate/prostatectomy bed local recurrences. Systemic therapy will be administered indefinitely, consistent with current guidelines. The primary study endpoint is castrate-resistant prostate cancer-free survival. Key secondary endpoints include clinical and radiographic progression free survival, overall survival, toxicity, and quality of life outcomes:

PERSIAN is a randomized phase II trial of recurrent oligometastatic, hormone-sensitive patients (<5 non-visceral lesions). Eligible patients will undergo 1:1 randomization to apalutamide + ADT +/- SBRT to all visible lesions. The primary outcome is 6-month complete biochemical response. The trial design and key secondary endpoints are illustrated below:

The POSTCARD GETUG P13 is a French randomized phase II trial that is randomizing patients with recurrent oligometastatic disease following primary local therapy with curative intent to either SBRT alone (to all visible metastases) or SBRT + durvalumab. Oligometastasis is defined as ≤5 bone or lymph node metastases on ⁶⁸Ga-PSMA PET/CT or ≤3 bone or lymph node metastases on ¹⁸F-choline PET/CT. The primary endpoint is two-year progression-free survival, with key secondary endpoints of androgen deprivation therapy free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response.⁸

Incorporating PSMA-PET/CT into the MDT Paradigm

The next ‘frontier’ of MDT trials is incorporating PSMA-PET/CT for staging oligometastatic patients and determining eligibility for MDT. Given the increased sensitivity of PSMA-PET/CT compared to conventional imaging,¹⁰ it is likely that this may lead to a ‘stage migration’ phenomenon, where future cohorts of oligometastatic prostate cancer patients, matched for the same number of metastatic lesions, have more favorable prognoses. However, there has been a shift away from defining the ‘upper limit’ of oligometastatic disease by the number of metastatic lesions. A recent survey of participants from the ESTRO-ASTRO consensus conference demonstrated that the majority of respondents concur that the ‘upper limit’ of oligometastatic disease should be defined by the ability to safely deliver curative intent metastasis-directed radiotherapy and not by the number of metastatic lesions.

Existing evidence suggests that PSMA-PET/CT provides additional information in patients with evidence of recurrent oligometastatic disease on conventional imaging. In the ORIOLE trial, as highlighted above, pre-treatment ¹⁸F-DCFPyL-PET/CT was performed in all patients assigned to the MDT arm (n = 36). Of the 36 patients treated with SBRT, 16 (44.4%) had baseline PET-avid lesions that were not included in the treatment fields. These patients had significantly worse 6-month progression rates of 38% compared to those without untreated lesions (5%; p = 0.03). Furthermore, those with untreated sites of disease had higher rates of new metastases (per conventional imaging) at 6 months (62.5% versus 15.8%, p = 0.006), and worse median distant metastasis-free survival of 6 versus 29 months (HR: 0.19; 95% CI: 0.07–0.54, p < 0.001). These results highlight the importance of targeting all sites of disease, and the value of PSMA PET/CT for defining this with increased sensitivity compared to conventional imaging.³

A single arm phase II study evaluated the role of MDT (SBRT or surgery) in 37 patients with a rising PSA (0.4–3 ng/ml) following maximal local therapy (radical prostatectomy + adjuvant/salvage radiotherapy) who had not received prior salvage hormonal therapy and had negative conventional imaging, but evidence of oligometastasis on ¹⁸F-DCFPyL PET-MR/CT. Ten and 27 patients underwent surgery and SBRT, respectively. At a median follow-up of 16 months, the overall response rate was 60%, including 22% who had biochemical ‘no evidence of disease. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed.¹¹

MDT for De Novo Oligometastatic Hormone-sensitive Prostate Cancer

There are numerous ongoing trials evaluating the role of MDT in combination with systemic therapy in the de novo oligometastatic hormone-sensitive setting. In this section, we will highlight key trials in this space.

SOLAR (NCT03298087) is a single arm phase II trial of 28 patients with de novo M1a/b disease and 1–5 radiographically visible M1 lesions (majority detected via PSMA PET-CT) who all underwent radical local treatment, intensified systemic therapy for six months (leuprolide, abiraterone acetate with prednisone, apalutamide), and metastasis-directed SBRT. Radical local therapy was either radical prostatectomy (n = 12) with lymph node dissection and postoperative radiotherapy (for ≥pT3a, N1, or positive margins) or radical radiotherapy (n=12) directed to the prostate, seminal vesicles, and pelvic lymph nodes. The initial results of this trial were presented at GU ASCO 2024. At a median follow-up of 30 months, 62% of patients completed all planned systemic therapy without dose modification. Of the 22 patients with >6 months follow-up after testosterone recovery, 86% remained free of any progression, defined as an undetectable serum PSA after radical prostatectomy or <2 ng/ml after radical radiotherapy. Grade 2 and 3 toxicities for primary tumor therapy were 46% and 4%, respectively. There were no grade 2–3 toxicities relating to SBRT.¹²

PLATON (NCT03784755) is a two-arm phase II RCT exploring sequential treatment with ADT +/- chemotherapy followed by cytoreductive prostatectomy or external beam radiotherapy and then SBRT for oligometastases in 410 men. The comparator arm consists of systemic therapy alone, although low-volume men will be allowed to receive conventional local prostate radiotherapy. The primary study outcome is failure-free survival:

IP2-ATLANTA (NCT03763253) is a three-arm phase II randomized trial exploring sequential systemic, local, physical cytoreductive therapy and finally SBRT versus standard of care in 918 men with any-volume metastatic disease. All patients will receive doublet systemic therapy (ADT + docetaxel or enzalutamide or abiraterone). Patients in experimental arm 1 will receive minimally invasive ablative therapy +/- lymph node dissection, whereas those randomized to experimental arm 2 will receive local external beam radiotherapy +/- lymph nodes or radical prostatectomy +/- pelvic lymph node dissection. Patients in both experimental arms will further receive SBRT to oligometastases following receipt of of systemic and local treatment. Patients in the control arm will receive planned systemic therapy only, although patients with low-volume metastases will be eligible for prostate external beam radiotherapy:¹³

Finally, TERPs (NCT05223803) is a phase II trial of patients with de novo oligometastatic disease (<3 on conventional imaging or <5 on PET/CT) who will be randomized 1:1 to best systemic therapy + primary prostate radiotherapy +/- MDT (SBRT). The primary study endpoint is two-year failure-free survival.¹⁴

Conclusions and Future Directions

MDT has emerged as a guideline-recommended treatment option for prostate cancer patients with oligometastatic disease. The evidence to date suggests that MDT can be used in lieu of systemic therapy to delay time-to-hormone therapy or in combination with systemic therapy as a consolidative measure. The latest NCCN guidelines recommend considering SBRT for MDT in oligometastatic patients when ablation is the goal or in oligometastatic patients with limited progression or limited residual disease on otherwise effective systemic therapy (i.e., consolidation), where progression free survival is the goal.

The next ‘frontier’ of clinical trials for MDT will be evaluating its efficacy and safety in patients with PSMA-PET/CT-defined oligometastases and defining its role in the de novo metastatic hormone-sensitive setting. The results of these exciting trials will become available over the next few years.

Published August 2024

Introduction

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

Introduction

Figure 1: The current landscape of FDA combination approvals in Metastatic Hormone Sensitive Prostate Cancer (mHSPC)^1-12 

Thus, this has changed the standard of care for treatment intensification for these men. This article will focus a discussion on the implementation of treatment for Metastatic Hormone Sensitive Prostate Cancer (mHSPC) in North America, specifically highlighting the landscape and challenges of treatment intensification, and the importance of disease volume and timing of metastasis for selecting the optimal treatment in the mHSPC disease space.

The Enigma of (Lack of) Treatment Intensification

Despite the approval and availability of multiple mHSPC treatment intensification strategies, there remains a clear underutilization of these combination strategies in real-world practice. The following discussion will highlight several of the key studies looking at contemporary treatment intensification across several North American jurisdictions.

Ryan et al. reported treatment utilization trends of mHSPC patients between January 2014 and July 2019 from two large U.S databases: (i) Optum’s de-identified Clinformatics Data Marta Database (COM/MA), which includes claims from commercial and Medicare Advantage plans for 13 million people across the United States and (ii) Centers for Medicare & Medicaid Services-sourced Medicare Fee-for-Service (FFS) Research Identifiable Files Sample.¹³  A total of 19,841 mHSPC patients (6,517 COM/MA and 13,324 Medicare-FFS) were identified with a median follow up of 9.6 – 10.5 months. Notably, 38% of COM/MA and 48% of Medicare-FFS patients remained untreated or deferred treatment during the study period, whereas 45% and 46%, respectively, were treated with first line ADT monotherapy only. Abiraterone acetate or docetaxel was used as first line therapy in 13% (COM/MA) and 2%

(Medicare-FFS) of patients. Approximately 43% and 38% of patients, respectively, only received ADT monotherapy (with or without a first-generation androgen signaling inhibitors) during the entire mHSPC period despite the availability of other more potent therapies. It is important to note that apalutamide and enzalutamide were added to evidence-based guidelines as mHSPC treatments after the end of the study period (July 31, 2019) and were not considered as mHSPC therapy in the current study. When stratified by year of index date, in the COM/MA database, treatment with first line ADT monotherapy decreased numerically from 48% to 43% among patients diagnosed with mHSPC in 2015 – 2017 versus 2018 – 2019. While the overall use of abiraterone or docetaxel remained similar in the two periods (12% - 14%), the relative use of abiraterone acetate increased among patients diagnosed in 2018 - 2019 (10%) versus 2015 - 2017 (5%), whereas the use of docetaxel decreased in 2018 - 2019 (4%) compared with 2015 – 2017 (7%).

Figure 2: First line therapy in patients with mHSPC by year of index data in the Clinformatics Data Marta Database¹³ 

Analysis from the Veterans Health Administration (VHA) database was reported by Freedland et al.¹⁴  for 1,395 mHSPC patients treated between April 2013 and March 2018. Across the five-year study period, 63% of patients received ADT alone as first line treatment while ADT + non-steroidal anti-androgen was used in 24%, ADT + docetaxel in 8%, and ADT + abiraterone for the remaining 5%. Treatment trends over time did demonstrate an overall decrease in ADT only (66% to 60%) or ADT + non-steroidal anti-androgen (31% to 17%) utilization between 2014 and 2017-2018, with a corresponding increase in utilization of ADT+ docetaxel (3% to 9%) and ADT + abiraterone (1% to 15%). Nonetheless, despite increased adoption of treatment intensification in VHA mHSPC patients, there remains a clear underutilization of appropriate treatment intensification.

Figure 3: Treatment trends over time among patients with mHSPC in the Veterans Health Administration¹⁴

A comparison of patients in the four treatment groups demonstrated that patients receiving ADT and docetaxel, compared to the ADT only cohort, were younger (65.8 versus 73.4 years) and had fewer comorbidities (National Cancer Institute comorbidity score 1.1 versus 1.5), but had greater disease burden in terms of higher PSA (338.1 ng/ml versus 256.4 ng/ml) and overall metastatic burden. ADT + abiraterone patients were older (75.3 versus 73.4 years), generally had fewer cardiovascular comorbidities and lower PSA (238.3 versus 256.5 ng/ml) but had increased metastasis (other sites including bone: 80% versus 73%).

A combined analysis from the VHA and Medicare database was presented at ESMO 2022. The authors identified 33,641 and 5,561 men in the Medicare and VA cohorts, respectively. Similar to the prior report by Freedland et al.,    ¹⁴  the authors demonstrated that the proportion of patients receiving treatment intensification with novel hormonal therapy or docetaxel increased over time, although by 2018/2019, still less than one third of patients with mHSPC received first line ADT plus docetaxel or ADT plus a novel hormonal agent.

Figure 4: Utilization of first line treatment intensification over time for mHSPC patients in the VHA and Medicare databases

While there were changes in treatment approaches between 2010 and 2014, the authors did not find any changes in overall survival in 2012–2014 compared with 2010–2011, though there was improvement in overall survival by 12% and 15% in the Medicare and VA cohorts, respectively, in 2015–2018/2019 versus 2010–2011, after adjusting for baseline characteristics, suggesting that diffusion of these intensified treatment approaches provides a population-level survival benefit.

Figure 5: Overall survival for mHSPC patients in the VHA and Medicare databases

A Medicare analysis of treatment intensification trends among racial minorities was presented by Freedland et al. at ASCO 2021. Compared to White, non-Hispanic men, Black men were less likely to receive treatment intensification (ADT + docetaxel or novel hormonal therapy) during 2010-2014 (2.6% versus 3.2%), 2015-2016 (8.7% versus 10.4%), and 2017 (14.2% versus 15.1%).

Using provincial data from Ontario, Canada, Wallis et al.¹⁵  identified 3,556 patients diagnosed with de novo mHSPC between 2014 and 2019. Of note, 78.6% of patients received ADT alone (with or without an anti-androgen), 11.2% received treatment intensification with docetaxel, 1.5% received abiraterone acetate and prednisone, with the remaining 8.7% receiving a “non-ADT” regimen. Patients receiving docetaxel were comparatively younger (mean age 72.6 years) and healthier (mean Charlson Comorbidity Index score of 0.15). The median PSA at diagnosis was lower among patients who received conventional ADT (88 ng/mL) compared with ADT intensification regimens (121 ng/mL and 152 ng/mL for the abiraterone and docetaxel cohorts, respectively). A time-stratified analysis representing the uptake of ADT intensification regimens before and after the pivotal 2017 LATITUDE trial,⁸  demonstrated that abiraterone acetate plus prednisone prescriptions increased from 0.5% to 3% in the pre- versus post-LATITUDE period, respectively, whereas docetaxel treatment dropped from 12% to 10%. As was reported by Ryan et al.¹³, these data suggest that the pivotal data from LATITUDE and STAMPEDE resulted in a substitution of intensification approach (from docetaxel to abiraterone) rather than a broadening of the patient population receiving treatment intensification.

Given the underwhelming utilization of treatment intensification for mHSPC patients in the real-world setting, barriers to improved adoption need to be further understood. At ASCO 2022, Freedland et al. provided the first granular assessment as to reasons for or against treatment intensification. This study examined data from medical charts of patients initiating mHSPC treatment from July 2018 to November 2021 based on a retrospective review of multiple US academic/community practices. This was a survey of oncologists and urologists who treated these patients to provide reasons for treatment choices, including PSA goals and explicit reasons for not prescribing novel hormonal agents. This analysis included 621 patients who were treated by 65 oncologists and 42 urologists. In the first line setting, most mHSPC patients received ADT ± non-steroidal anti-androgen alone (69%), while treatment intensification rates with ADT + novel hormonal agent (26%) or ADT + chemohormonal therapy (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.

When the physicians were queried about reasons for not using novel hormonal agents, the most frequently cited reasons were:

1. “Novel hormonal therapy would need to have a better/more tolerable side effect profile/fewer adverse events than my chosen regimen” (38%)
2. “I would need to have seen clinical trial evidence of survival improvements on novel hormonal therapies including a wider range of prostate cancer patients” (31%)
3. “Novel hormonal therapies would need to be reimbursed by patients’ insurance” (26%)

Figure 6: Reasons given by providers for not using novel hormonal therapy

Regarding treatment goals for PSA response, physicians more frequently reported a relative reduction than an absolute PSA reduction (85% versus 51%). Oncologists considered a median PSA reduction of 50% (IQR 25-75%) adequate versus 75% (IQR 50-90%) among urologists. Urologists were more likely to utilize treatment intensification in the first line setting or subsequently in patients who were still castration-sensitive (p < 0.01). Furthermore, physicians who aimed for deeper PSA reductions of 75-100% were more likely (OR: 1.63, p = 0.034) to provide treatment intensification in the first-line setting compared with physicians with less aggressive PSA goals (0 – 49%). The authors concluded that physician survey results suggest that perceptions of tolerability and lack of efficacy and financial considerations affect novel hormonal therapy use. In practice, non-guideline driven PSA reduction goals are associated with low rates of treatment intensification, and these results clearly demonstrate the need for further medical education.

Treating Implementation: Using Disease Volume and Timing of Metastasis to Guide Treatment Selection

Patients with mHSPC at the time of diagnosis are defined as having de novo or synchronous metastatic disease. Additionally, there is a subset of men initially diagnosed with non-metastatic disease, many of whom had 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.¹⁶  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.¹⁷ 

As such four distinct subgroups become clinically relevant (median OS per CHAARTED and GETUG-15 among men receiving ADT alone, i.e., the control groups in these trials):

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

While early, aggressive treatment intensification with triplet regimens, with or without primary radiotherapy, may seem attractive in this cohort of patients to maximize survival outcomes, the reality is that such “maximal” treatment intensification is unnecessary in the majority of these patients. Furthermore, treatment toxicity, both from a pathophysiologic and financial standpoint, must be considered in these patients. As such, a nuanced approach to the treatment of such patients, guided by the aforementioned four presentations (synchronous high volume, synchronous low volume, metachronous high volume, and metachronous low volume) is needed. Arguably, over the next several years, particularly until reliable biomarkers become available, this will be how most clinicians implement treatment for mHSPC patients in North America.

Synchronous High Volume mHSPC

Based on the results from PEACE-1¹⁸  and ARASENS¹⁰, as well as subgroup analysis from ENZAMET³, it appears that this patient cohort, particularly those who are chemotherapy-fit, are most likely to benefit from triplet therapy with docetaxel + androgen receptor pathway inhibitor (ARPI) + ADT.

The PEACE-1 trial¹⁸  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 rPFS with a median rPFS of 1.6 years in the standard of care arm and 4.1 years in 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 in the standard of care plus abiraterone + prednisone + ADT arm (HR: 0.58, 95%: CI 0.39 to 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 5.1 versus 3.6 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 overall survival 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.

ADT + Docetaxel + Darolutamide

The ARASENS trial evaluated the addition of darolutamide to standard of care therapy consisting of ADT + docetaxel versus ADT + docetaxel alone.¹⁰  Darolutamide + ADT + docetaxel prolonged overall survival for high volume mHSPC (HR 0.69, 95% CI 0.57-0.82).¹⁹ 

Figure 7: Overall survival of darolutamide + ADT + docetaxel vs ADT + docetaxel for high volume disease patients in the ARASENS trial

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. Updated results of the ENZAMET trial were published in 2023⁴, with survival outcomes stratified by disease volume (high versus low) and presentation (synchronous versus metachronous). Based on these subgroup analyses, patients with synchronous, high-volume mHSPC had a clinical benefit, albeit not statistically significant, for ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen whether they were planned to have docetaxel (HR: 0.79, 95% CI: 0.57 to 1.10) or in the intention to treat analysis (HR: 0.70, 95% CI: 0.47 to 1.04).

Figure 8: Overall survival in ENZAMET for patients with synchronous high volume mHSPC

Results from these three trials provide strong evidence to support the use of a triplet 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 ARPI addition to standard ADT. 

Synchronous Low Volume mHSPC

For patients with low volume disease, there appears to be a potential late clinical benefit to triplet therapy of ADT + docetaxel + darolutamide, however, with few events and additional follow-up time likely required, there is no statistically significant benefit at this point (HR: 0.68, 95% CI: 0.41 to 1.13)

Figure 9: Overall survival of darolutamide + ADT + docetaxel vs ADT + docetaxel for low volume disease patients in ARASENS

Similarly, for patients treated in the ENZAMET trial with low volume synchronous disease, there was no benefit for ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen for those planned for docetaxel (HR: 0.57, 95% CI: 0.29 to 1.12). 

Figure 10: Overall survival of enzalutamide + ADT + docetaxel vs ADT + docetaxel + non-steroidal anti-androgen for synchronous low volume disease patients

ARATs + ADT

There is consistent evidence across all major published phase III trials to support an overall survival benefit to the addition of an ARPI to ADT in patients with synchronous low-volume disease. This is reflected, as follows:

• LATITUDE (abiraterone + ADT versus ADT alone; all de novo): HR 0.72, 95% CI 0.47 to 1.10⁹
• STAMPEDE (abiraterone + ADT versus ADT alone; >90% de novo): HR 0.64, (95% CI 0.42 to 0.96)¹⁰
• TITAN (apalutamide + ADT versus ADT alone; 10% prior docetaxel): HR 0.52, 95% CI 0.35 to 0.79¹¹
• ENZAMET (enzalutamide + ADT versus non-steroidal antiandrogen + ADT): HR 0.58, 95% CI 0.32 to 1.04    ⁴ 
• ARCHES (enzalutamide + ADT versus ADT alone; 18% prior docetaxel): HR 0.66, 95% CI 0.43 to 1.03¹²

As such, ARPI addition to ADT has become the backbone of any treatment approach in patients with synchronous, low volume prostate cancer.

Primary Radiotherapy for synchronous, low volume mHSPC patients

Beyond systemic treatment intensification, local prostate-directed therapy may allow for local treatment intensification. While a surgical approach using radical prostatectomy has been described, high quality data are limited to radiotherapy. Of note, the SWOG 1802 trial is accruing patients with a surgical arm in the setting of mHSPC to further assess the impact of cytoreductive prostatectomy in this disease space. Three trials to date have evaluated the role of local radiotherapy in the prostate in patients with mHSPC.

STAMPEDE (Arm H) was an open label, randomized controlled phase III trial of 2,061 men at 117 hospitals across Switzerland and the UK.¹¹  This trial randomized patients with de novo mHSPC in a 1:1 fashion to standard of care + radiotherapy or standard of care alone. Men allocated to radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomization. The primary outcome of this trial was overall survival. Subgroup analysis by metastatic volume (CHAARTED criteria) was planned a priori. Median follow up for STAMPEDE Arm H was 37 months, median patient age was 68 years, and median PSA was 97 ng/ml. 18% of patients received early docetaxel. In the overall cohort, radiotherapy improved failure-free survival (HR: 0.76, 95% CI:0.68 to 0.84) but not overall survival (HR: 0.92, 95% CI: 0.80 to 1.06). However, when stratified by metastatic burden, overall survival benefits were seen 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 49.1.¹¹  

Figure 11: Overall survival in low metastatic burden patients with mHSPC and radiotherapy to the prostate primary in STAMPEDE Arm H

HORRAD was a multicenter prospective randomized clinical trial of 432 patients with previously untreated, de novo mHSPC at 28 centers across The Netherlands between November 2004 and September 2014.    ²⁰  All eligible patients had a PSA >20 ng/ml and documented bone metastases on bone scan. Patients were randomized in a 1:1 fashion to either ADT with EBRT or ADT alone, with a primary endpoint of overall survival. The median PSA was 142 ng/mL and over a median follow up of 47 months, the median overall survival was non-significantly different at 45 months in the radiotherapy + ADT arm compared to 43 months in ADT alone arm (HR: 0.90, 95% CI: 0.70 to 1.14). 

Results of the efficacy and safety of prostate radiotherapy for patients with low volume, de novo mHSPC from the PEACE-1 trial were recently presented at ASCO 2023. The addition of prostate radiotherapy to standard of care + abiraterone was associated with significant rPFS benefits (median 7.5 versus 4.4 years, p=0.02). Conversely, addition of radiotherapy to standard of care therapy alone was not associated with rPFS benefits (median 2.6 versus 3.0 years; HR: 1.11, 95% CI: 0.67 to 1.84, p=0.61).

The addition of prostate radiotherapy to either standard of care alone or standard of care therapy + abiraterone was not associated with overall survival improvements. In the standard of care + abiraterone arms, addition of prostate radiotherapy was associated with modest, non-significant OS benefits (HR: 0.77, 95% CI: 0.51 to 1.16, p=0.21). Similarly, addition of prostate radiotherapy to standard of care alone did not improve overall survival (HR: 1.18, 95% CI: 0.81 to 1.71, p=0.39).

Interestingly, addition of prostate radiotherapy to standard of care +/- abiraterone in the low-volume cohort was associated with significant improvements in the time to serious genitourinary events (p=0.0006). This overall benefit was consistent irrespective of whether patients had prostate radiotherapy added to standard of care + abiraterone (p=0.003) or standard of care therapy alone (p=0.048). 

The majority of patients with synchronous, low volume mHSPC benefit from early systemic treatment intensification with ARPI addition to ADT. Such patients should also be offered primary radiotherapy to the prostate gland in the appropriate clinical settings. 

Metachronous High Volume mHSPC

Given that the PEACE-1 trial included patients with de novo mHSPC only, ARASENS and ENZAMET provide the available data to assess the benefit of triplet therapy in this mHSPC subgroup. In ARASENS, the overall survival for patients with high volume mHSPC had a prespecified subgroup analysis for assessing recurrent (metachronous) disease (n =117) with a clinical benefit, but no statistically significant benefit (HR: 0.70, 95% CI: 0.39 to 1.24). In the ENZAMET trial, there was no benefit to treatment intensification for triplet therapy (HR: 1.18, 95% CI: 0.66 to 2.11).

Figure 14: Overall survival of enzalutamide + ADT + docetaxel vs ADT + docetaxel + non-steroidal anti-androgen for metachronous high volume disease patients in ENZAMET

When considering patients with mHSPC along a risk continuum, from good risk (metachronous low volume: 8-year median overall survival with ADT alone) to poor risk (synchronous high volume: 3-year median overall survival with ADT alone), patients with synchronous low volume and metachronous high volume (median overall survival: 4.5 years with ADT alone) mHSPC may both be considered as intermediate risk disease. As such, the clinical treatment approach for these two subgroups has seen significant overlap. ARPI + ADT have similarly served as the backbone for treatment of these patients. Patients with metachronous, high volume mHSPC have historically accounted for only a small proportion of patients in the published phase III trials, and as such, post-hoc analyses have been underpowered for evaluating this subgroup. Results from the ARCHES trial have demonstrated a 23% decreased hazard of overall mortality in this subgroup with addition of enzalutamide to ADT (HR: 0.77, 95% CI: 0.39 to 1.50).⁵  Similar results were found in the ENZAMET trial (HR: 0.73, 95% CI: 0.37 to 1.44).

Results from the STOPCAP M1 collaborative meta-analysis of individual patient data from GETUG-15, STAMPEDE, and CHAARTED demonstrated that docetaxel addition to ADT in patients with metachronous, high volume prostate cancer is associated with significant improvements in overall survival (HR: 0.64, 95% CI: 0.42 to 0.99),²¹  which was consistent on follow-up analyses.²² 

 Given the relatively increased toxicity with taxanes, along with a subset of patients being “chemotherapy unfit”, it appears that doublet therapy with an ARPI + ADT is the favored treatment approach in patients with metachronous high volume disease, with docetaxel reserved for select patients with higher volume of disease.

Metachronous Low Volume mHSPC

Similar to metachronous high volume patients, the subgroup analyses of triplet therapy trials assessing metachronous low volume mHSPC patients remain limited. In ARASENS, metachronous low volume disease patients (n = 51) had too few overall mortality events to provide adequate samples size for powered analyses. For the ENZAMET trial, the HR for metachronous low volume patients was 0.64 (95% CI: 0.18 to 2.28).

Subgroup analyses have consistently demonstrated an overall survival benefit to ARPI addition in patients with low volume mHSPC. Results from the ARCHES trial demonstrated a 37% improved hazard of overall survival with enzalutamide addition to ADT in patients with metachronous low volume mHSPC (HR: 0.63, 95% CI: 0.26 to 1.54). From the ENZAMET trial, patients with metachronous low volume disease had a clinical and statistically significant benefit (HR of 0.47, 95% CI: 0.28 to 0.79).

Importantly, there is consistent evidence against the use of docetaxel in this mHSPC subgroup. Results from the CHAARTED trial demonstrated a minimal overall survival in this subgroup (HR: 0.77, 95% CI: 0.51 to 1.18). Furthermore, results from the STOPCAP meta-analysis using CHAARTED and GETUG-AFU15 data demonstrated no overall survival benefit to docetaxel addition (HR: 1.07, 95% CI: 0.75 to 1.54).

Table 1: A summary of overall survival by volume and timing of metastases from the key registration

Conclusions

Published November 2023

Part of an Independent Medical Education Initiative Supported by  LOXO@Lilly

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).

Introduction

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

ADT + Docetaxel

ADT + Abiraterone/Prednisone

ADT + Apalutamide vs ADT

• High: HR: 0.70 (95% CI: 0.56-0.88)
• Low: HR: 0.52 (95% CI: 0.35-0.79)

• Synchronous: HR: 0.68 (95% CI: 0.55-0.85)
• Metachronous: HR: 0.39 (95% CI: 0.22-0.69)

ADT + Enzalutamide vs ADT

• Yes: HR 0.82 (95% CI 0.63 to 1.06)
• No: HR 0.60 (95% CI 0.47 to 0.78)

• Low: HR 0.54 (95% CI 0.39 to 0.74)
• High: HR 0.79 (95% CI 0.63 to 0.98)

• Synchronous: HR 0.70 (95% CI 0.56 to 0.87)
• Metachronous: HR 0.71 (95% CI 0.52 to 0.98)

• 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

ADT + Docetaxel + Darolutamide

Specific Considerations for Low Volume mHSPC Patients

Synthesizing the Timing of Metastasis and Volume of Disease Relationship

Introduction

Introduction