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Introduction

Bladder cancer remains the sixth most commonly diagnosed cancer in the United States, with an estimated 82,290 incident cases in 2023.¹ Because of the persistent recurrence risk of NMIBC in a highly comorbid population, there has been an FDA-led drive towards developing novel treatment options for these patients. The following article will highlight recent advances in this disease space with a specific focus on the oncolytic adenovirus agent cretostimogene grenadenorepvec, and the registration trial in intermediate risk non-muscle invasive bladder cancer (NMIBC), PIVOT-006. 

Introduction

Immune checkpoint inhibitors have emerged as a guideline-recommended first line treatment option for patients with cisplatin-ineligible, metastatic urothelial carcinoma of the bladder and as second line therapy for patients with metastatic disease progressing during, or after, platinum-based combination chemotherapy.¹ Pembrolizumab, a Programmed Death-1 (PD-1) inhibitor, has been recently approved by the US Food and Drug Administration for the treatment of patients with Bacillus Calmette Guerin (BCG)-resistant non-muscle invasive bladder cancer (NMIBC), based on the results of the KEYNOTE-057 trial.^2,3

Given that patients with NMIBC receiving adjuvant BCG post-TURBT have estimated risks of disease recurrence and progression of 40% and 10%, respectively,⁴ the BCG naïve NMIBC space may provide an opportunity to move these agents up even further along the bladder cancer disease spectrum. In this Center of Excellence article, we will summarize the current state of the evidence for ongoing trials evaluating immune check point inhibitors and other immune priming interventions in combination with BCG for the treatment of BCG naïve NMIBC.

Pembrolizumab + BCG

Previous studies have demonstrated that programmed cell death ligand 1 (PD-L1) expression is significantly increased in BCG-induced bladder granulomata of patients with BCG unresponsive disease.⁵ As such, it has been hypothesized that the addition of a PD-1 inhibitor, such as pembrolizumab, may overcome this potential underlying mechanism of resistance.

The combination of pembrolizumab + BCG has previously been evaluated in the setting of a phase I trial for patients with BCG unresponsive NMIBC. This combination was determined to be relatively safe, and the 13 evaluable patients had a 3-month complete response rate of 69%.⁶

KEYNOTE-676 is a randomized, comparator-controlled trial evaluating the efficacy and safety of pembrolizumab + BCG in patients with high-risk NMIBC (T1, CIS, high grade Ta) who underwent cystoscopy/transurethral resection of bladder tumor ≤12 weeks before randomization and had not received BCG within the preceding two years. Patients will be randomly assigned 1:1:1 to receive:

• Pembrolizumab 400 mg IV every 6 weeks + BCG reduced maintenance (≤ 6 months)
• Pembrolizumab 400 mg IV every 6 weeks + BCG full maintenance (≤ 18 months)
• BCG monotherapy with BCG full maintenance

The trial schema for KEYNOTE-676 cohort B is as follows:


The primary endpoint for this trial is event-free survival, defined as the time from random assignment to the first occurrence of any of the following:

• High-grade Ta, CIS, or any T1 disease of the bladder
• High-risk disease (high-grade Ta, CIS, or ≥T1) of the urethra or upper tract
• Locally advanced/metastatic disease determined by blinded independent central review
• Death from any cause

The secondary endpoints will include complete response rate by blinded independent central review, duration of response, disease-specific survival, time to cystectomy, overall survival, and safety.⁷ As follows is a geographical representation of the countries currently enrolling patients in KEYNOTE-676:

Additionally, a single arm, phase II trial (NCT03504163) from the Memorial Sloan Kettering Cancer Center is evaluating the combination of BCG + pembrolizumab in patients with high-risk T1 bladder cancer, with an additional exploratory cohort of patients with upper tract disease. This study will plan to enroll 37 patients, who will receive pembrolizumab 400 mg IV at 6-week intervals (total 9 doses), with BCG (TICE strain, 50 mg) administered once weekly for 6 weeks as induction, followed by maintenance consistent with standard clinical practice. BCG will be started on week 3 after the first infusion of pembrolizumab to allow for the initial priming of T cells to further enhance the effects of BCG treatment. The primary outcome is the proportion of patients who remain free of high-grade disease recurrences at 6 months post-treatment initiation.⁸

Atezolizumab + BCG

BladderGATE (NCT04134000) is a phase Ib-II trial evaluating the safety and efficacy of atezolizumab (anti-PD-L1) + BCG in patients with high-risk NMIBC, who are either BCG-naïve or had not received BCG in the preceding two years. Patients in this trial will receive either:

• Induction BCG with 1 instillation every week + IV atezolizumab 1,200 mg every 3 weeks (Dose level 0)
• Induction BCG with ½ instillation every week + IV atezolizumab 1,200 mg every 3 weeks (Dose level -1)

Following induction, BCG will be administered at weeks 13-15, 25-27, and 49-51, with atezolizumab concurrently administered for up to 1 year. Patients were accrued to each dose level in cohorts of 10 patients until the maximum tolerated dose is achieved (dose at which < 4 out of 10 patients experience dose-limiting toxicity). The interim safety results were recently presented at ASCO 2023. This analysis included 34 patients, with no dose-limiting toxicities reported in the first 10 patients included at dose level 0. The most frequent grade 3-4 adverse events were:

• Asthenia (9%)
• Myocarditis (3%)
• Immune-mediated hepatitis (3%)
• Hyponatremia (3%)
• Encephalopathy (3%)
• Guillain-Barre syndrome (3%)

Two patients discontinued the study treatment due to immune-mediated Grade 3 hepatitis and pneumonitis, respectively.⁹

ALBAN (AFU-GETUG 37; NCT03799835) is a phase III trial across 30 centers in France evaluating the efficacy and safety of atezolizumab given in combination with BCG versus BCG alone in patients with BCG naïve, high-risk NMIBC (T1, high-grade, and/or CIS). Eligible patients will be randomized 1:1 to:

• Arm A: BCG alone with six weeks induction followed by three weekly maintenance instillations at 3, 6, and 12 months
• Arm B: BCG + atezolizumab (1,200 mg IV every 3 weeks for up to 1 year)

The primary endpoint is recurrence-free survival in the intent-to-treat population, with secondary efficacy endpoints of overall survival, progression-free survival, complete response, disease worsening, quality of life, and safety outcomes. Study enrollment began in December 2018 with a target of 614 patients.¹⁰

Durvalumab + BCG

POTOMAC (NCT03528694) is an open label, multicenter, randomized trial evaluating the combination of durvalumab (anti-PD-L1) and BCG in BCG-naïve patients with high-risk NMIBC (any high-grade disease, T1, CIS, LG Ta if >3 cm, recurrent, and multifocal). This trial will randomize 1,018 patients to:

• BCG induction + maintenance for 24 months
• BCG induction + maintenance + durvalumab (1,500 mg every 4 weeks for 13 cycles)
• BCG induction only (no maintenance) + durvalumab

The study design is as follows:


The primary study endpoint is disease-free survival, with secondary endpoints including the proportion of patients alive and disease-free at 24 months, 5-year overall survival, pharmacokinetics, immunogenicity, safety, tolerability, and health-related quality of life.¹¹

Sasanlimab + BCG

Sasanlimab is an anti-PD-1 monoclonal antibody that has demonstrated an acceptable safety profile and promising clinical activity in patients with locally advanced or metastatic urothelial carcinoma, within the context of a phase 1 trial.¹² The phase 3 CREST study (NCT04165317) Cohort A will evaluate subcutaneous injection sasanlimab in patients with BCG naive NMIBC. Patients in this cohort will be randomized to one of three arms:

• Arm A: Sasanlimab + BCG induction + maintenance
• Arm B: Sasanlimab + BCG induction only
• Arm C: BCG induction + maintenance

This trial will assess for between-arm differences in event-free, disease-specific, and overall survivals, complete response rate, adverse events/safety profile, and health-related quality of life.¹³ Of note, On August 31, 2022, the Sponsor announced the discontinuation of enrollment to Part B (Cohort B), which enrolled participants with BCG unresponsive NMIBC. The decision to discontinue enrollment to Part B (Cohort B) was not made for safety reasons.¹⁴

Immune Priming: Intradermal BCG

The PRIME trial (SWOG S1612) is evaluating whether intradermal BCG inoculation may potentiate the immune effects of subsequent intravesical BCG instillations. This hypothesis was recently tested in a single arm trial that demonstrated that percutaneous BCG administered 21 days prior to intravesical instillation in patients with high-risk NMIBC boosted BCG-specific immunity at 3 months and increased the activation status of in vitro expanded circulating NK and γδ T cells and their cytotoxicity against bladder cancer cells.¹⁵

In the PRIME trial, the Tokyo BCG strain is being used for both intradermal inoculation and intravesical instillation in a three-arm design with TICE strain BCG also used as a standard of care comparator. This study was designed to test:

• The comparitive superiority between intravesical Tokyo strain BCG when combined with intradermal inoculation as compared to intravesical alone (arms 2 and 3)
• The non-inferiority of intravesical Toyko strain alone to intravesical TICE strain (arms 1 and 2).
  • TICE strain is currently the only strain that is FDA approved and in production in the USA (Armond-Frappier and Connaught are also FDA approved, but not currently in production). As such, if the Tokyo strain is found to be non-inferior to TICE, this may facilitate its subsequent FDA approval and increased the availability of additional BCG strains during the current shortage

The study design is as follows:


This trial has now fully accrued and is awaiting readout in the nearby future.

Conclusions

Numerous ongoing trials are evaluating the combination of BCG and an immune checkpoint inhibitor for patients with BCG naïve NMIBC. By inhibiting the PD-1/PD-L1 axis, it is hypothesized that these agents may help overcome underlying mechanisms of resistance inherent to BCG-resistant strains, and thus improve on the historic recurrence and progression rates observed with BCG treatment alone. Many of these trials have completed accrual, and we await the results of these combinatory trials in the upcoming years.

Introduction

Introduction

Bacillus Calmette Guerin (BCG) is currently guideline-recommended in the adjuvant setting for patients with intermediate or high-risk non-muscle invasive bladder cancer (NMIBC).¹ This is based on the results of numerous randomized clinical trials and meta-analyses demonstrating its ability to reduce the rates of disease recurrence and progression, compared to transurethral resection of bladder tumor (TURBT) alone or other adjuvant therapies.^2-5

Introduction

Since the United States Food and Drug Administration (FDA) approval of mitoxantrone in 1996¹ and docetaxel in 2004² for the treatment of patients with metastatic castrate-resistant prostate cancer, we have witnessed the approval of numerous additional agents/combinations in this disease space:

Introduction

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

Introduction

Introduction

Introduction

Introduction

Gemcitabine + Docetaxel

• 1 year: 60%
• 2 years: 50%
• 5 years: 30%

Device-assisted Administration of Intravesical Chemotherapy

• Cohort 1: TAR-200 + cetrelimab (PD-1 inhibitor)
• Cohort 2: TAR-200 alone (target sample size 50, currently enrolled: 23)
• Cohort 3: Cetrelimab alone (target sample size 50, currently enrolled: 24)

Radiofrequency-induced Thermochemotherapy

Hyperthermic Intravesical Chemotherapy

Photodynamic Therapy

Enfortumab Vedotin

Erdafitinib

Conclusions