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Introduction

Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard of care, guideline recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and disease progression.^1-3 However, despite adequate BCG, up to 50% of patients develop a BCG-refractory, relapsing, or failure disease state.⁴ Currently, radical cystectomy remains the gold standard approach in this setting.¹ However, many patients are either unfit or refuse cystectomy.

Given the shortage of options in this disease space, along with the modest efficacy of Valstar (21% complete response with a median response duration of one year),⁵ in 2018 the FDA issued a guidance document to promote the development of drugs and biologics for BCG-unresponsive NMIBC:⁶

• Persistent or recurrent CIS within 12 months of adequate BCG therapy
• Recurrent high-grade Ta/T1 disease within six months of completion of adequate BCG therapy
• High-grade T1 disease detected on the first evaluation following an induction BCG course

The focus of this Center of Excellence article is to highlight the currently available evidence and ongoing studies for Nogapendekin alfa-inbakicept (NAI; Anktiva, ie. N-803) in NMIBC in the BCG-unresponsive disease space, as well as other ongoing trials in progress for other indications.

QUILT-3.032: Initial Results

Impaired T-cell and cytotoxic cellular response play a key role in the development of BCG failure for patients with NMIBC. N-803 is an interleukin-15 (IL-15) superagonist that acts as an activation and proliferation factor for natural killer and effector/memory T-cells: 

Given that BCG has been shown to establish ‘trained immunity’ as the molecular basis for its immunotherapeutic effect in bladder cancer, it has been hypothesized that N-803 could further enhance the immune response by mediating a second, unrelated stimulus.

QUILT-3.032 is an ongoing, open label, multicenter, single arm trial that is evaluating intravesical N-803 + BCG or N-803 alone in patients with BCG-unresponsive, high-grade NMIBC⁷. This study includes three patient cohorts⁸:

• Cohort A (CIS +/- papillary disease): Intravesical N-803 (400 μg/instillation) + BCG (50 mg/installation) given once weekly for 6 consecutive weeks (induction)
• Cohort B (High grade Ta/T1 papillary disease): N-803 + BCG
• Cohort C (CIS +/- papillary): N-803 alone 

In this trial, surveillance included a cystoscopy + urinary cytology every 3 months for the first 24 months, followed by every six months thereafter until 60 months. Importantly, biopsy was mandated at week 12 in all patients, irrespective of cystoscopy or cytology findings. Re-induction was offered to patients without a complete response, conditional on the absence of T1 or worse disease in the specimen. These patients would then undergo a mandatory 6-month biopsy. The primary endpoints in Cohorts A and C were 3- and 6-month complete response, defined by one of the following three scenarios:

• Negative cystoscopy and cytology (including atypical cytology)
• Biopsy-proven benign or low-grade Ta disease and negative cytology
• Negative cystoscopy with malignant urinary cytology, if cancer found in the upper tract or prostatic urethra and random bladder biopsies were negative

In Cohort A (n = 82), a complete response was observed in 71% of patients (13/58 responders required a re-induction). Response rates were as follows:

• 3 months: 55%
• 6 months: 56%
• 12 months: 45%

The median duration of response in complete responders was 26.6 months. The 24-month progression-free, overall, and disease-specific survival rates were 85%, 94%, and 100% respectively.  

In 72 evaluable patients in Cohort B, the median disease-free survival was 19.3 months (95% CI 7.4 – NR), with disease-free survival rates as follows:

• 12 months: 55.4% (95% CI 42.0 – 66.8)
• 18 months: 51.1% (95% CI 37.6 – 63.1)
• 24 months: 48.3% (95% CI 34.5 – 60.7) 

The 24-months progression-free, overall, and disease-specific survival rates were 88.8%, 91.7%, and 97.7%, respectively.

In the 10 evaluable patients in Cohort C, a complete response at 3 months was observed in only 2 (20%) patients with N-803 alone. Of the 8 initial non-responders, 6 underwent re-induction with only 1 of these 6 patients demonstrating evidence of a complete response at 6 months. On the basis of protocol-defined stopping rules, the independent data monitoring committee recommended that cohort C be discontinued for futility.

The most common treatment-related adverse events with the combination of N-803 + BCG were lower genitourinary in nature (dysuria, pollakiuria, hematuria). The incidence of grade 3 or worse adverse events was 23%, most frequently hematuria and urinary tract infections (2% each). One patient experienced a grade 5 treatment-related adverse event (cardiac arrest with subsequent death) and 3 had evidence of immune-related adverse events:⁷ 

QUILT-3.032: After the Initial Results

On April 22, 2024, the Food and Drug Administration (FDA) approved N-803 + BCG for patients with BCG-unresponsive NMIBC with CIS +/- papillary tumors based on results from the QUILT-3.032 trial.

Quality of Life Assessment

In Cohort A, the mean baseline ECOG score was 0.183, with 82% of patients having a score of 0. Quality of life was measured by the EORTC QOL Questionnaire Core 30 (QLQ-C30) and QOL NIMBC-Specific 24 Questionnaire (QLQ-NMIBC24). During the study, hospitalizations for any reason remained low (0% - 6% per assessment). Moreover, participant quality of life from completion rate was high, with 90% or greater at most time points. There was a modest decrease in mean physical function and global health from baseline at all assessed on-study time points that became less by week 104: 

When responders (those with a complete response) were compared with non-responders, they showed less of a decrease in physical function and global health scores with time, although both parameters were higher at baseline for responders: 

At month 12, >3 prior TURBTs were significantly associated (p = 0.0729) with lower global health scores as compared to <= prior TURBTs. At month 6, achievement of complete response was associated (p = 0.0659) with higher physical function scores as compared to no complete response. No other baseline variable had a significant level of association: 

QUILT-3.032 Updated Results

At AUA 2024, Dr. Patrick Soon-Shiong presented updated results of the QUILT-3.032 trial. At the time of the data cutoff of November 30, 2023, patients with an ongoing complete response at month 25 and later, maintenance instillations were administered once a week for 3 weeks at months 25, 31, and 37 for a maximum of 9 additional instillations. In this highly pre-treated group, the complete response rate was 65%. Among patients who had received ≥12 prior BCG doses (n = 74), the complete response rate was 69%. Conversely, among those who received <12 doses of prior BCG, the complete response rate was 70%. A total of 53 patients were BCG-unresponsive/BCG-relapsed, and the complete response rate in this group was 72%. Thus, both BCG-unresponsive/BCG-refractory and BCG-unresponsive/BCG-relapsed had complete response rates comparable to the efficacy population. The median duration of response was 26.6 months (95% CI: 0.9 – not reached). By the Kaplan-Meier method, 61.3% of subjects had a duration of complete response lasting >12 months and 53.2% had a duration of >24 months.

Looking Ahead: QUILT-2.005 in BCG-Naïve Patents

Also at AUA 2024, Dr. Sandeep Reddy discussed the QUILT-2.005 trial comparing intravesical BCG in combination with N-803 to BCG alone in patients with BCG-naïve NMIBC. In phase 1 of this trial, there was durable complete remission among 9 patients with CIS and papillary NMIBC treated with BCG + N-803. As requested by the Agency, there was an unplanned interim analysis of the efficacy results in CIS patients for the phase 2 QUILT-2.005 trial, which showed an improvement in complete response rate over time and contribution of effect of N-803 inducing memory T-cells

The trial design for the phase IIb QUILT-2.005 is for participants to be randomized 1:1 to one of two independent treatment arms based on disease and ECOG status. Participants receive either intravesical 400 ug N-803/instillation + 50 mg BCG or BCG alone weekly for six consecutive weeks, followed by maintenance treatment for 3 consecutive weeks at 3, 6, 12, and 18 months. At 3 months, re-induction with another 6 weeks of therapy for eligible patients is an option. Cohort A of QUILT-2.005 will have CIS +/- Ta or T1 disease patients, and Cohort B will have high grade papillary Ta or 1 disease patients. Participants must have a diagnostic biopsy within 3 months of treatment start and a cystoscopy demonstrating no resectable disease within 6 weeks. Participants must be BCG-naïve (or last BCG > 3 years prior) and have not received more than a single post-operative dose of mitomycin C or gemcitabine following the most recent screening TURBT/biopsy.

The primary outcomes of QUILT-2.005 are complete response rate and disease free survival with the time frames of 12 and 24 months, respectively. The complete response rate for Cohort A and disease free survival for Cohort B will be compared between treatment arms using cystoscopy, confirmatory biopsy and urine cytology. Safety will be assessed by number/severity of treatment related adverse events over 48 months. As of April 2024, cohort A had enrolled 121 of 366 planned participants, and cohort B had enrolled 74 of 230 planned participants. 

N-803 + BCG Logistics and Insurance Coverage

In May 2024, it was announced that ImmunityBio had signed a global agreement with Serum Institute of India (the world’s largest manufacturer of vaccines) to supply ImmunityBio with BCG. The agreement covers manufacturing of standard BCG (approved outside of the US), as well as next generation recombinant BCG (undergoing testing), for the intended use in combination with N-803. Importantly, the aim of this deal is to increase the available supply of BCG and address shortages for the combination with N-803. Furthermore, there are plans to conduct clinical trials to study recombination BCG and standard BCG manufactured by Serum Institute in combination with N-803 for NMIBC.

As of August 2024, N-803 is approved for coverage by more than a dozen insurance plans (corresponding to ~100 million individuals), only months after the FDA approval in the US. Additionally, ImmunityBio has filed for EMA regulatory approval in the European Union, as well as approval to enroll patients in India for the QUILT-2.005 trial. Plans are also underway to apply for approval in South Africa to enroll patients in QUILT-2.005.

Conclusions

Results from the QUILT-3.032 trial in BCG-unresponsive NIMBC have led to the FDA approval of N-803 + BCG in 2024. Importantly, this combination therapy is now approved by several insurance plans and has been recognized as a therapeutic option in the NCCN guidelines. In light of the global BCG shortages, ImmunityBio has successfully partnered with Serum Institute of India to increase BCG availability. Results of the ongoing QUILT-2.005 trial in BCG naïve NMIBC are eagerly anticipated, with continued site expansion in the US, as well as India and potentially South Africa.

Published November 2024

Introduction

In November 2023, the United States Food and Drug Administration (FDA) approved enzalutamide, with or without concurrent leuprolide therapy, for conventional imaging-defined non-metastatic hormone-sensitive prostate cancer (M0 HSPC) patients with biochemical recurrence at high risk for metastasis.¹ This drug approval followed the publication of the EMBARK trial, a randomized phase III trial of biochemically recurrent patients who had high-risk disease, defined by a PSA doubling time (PSADT) ≤9 months and a PSA level of ≥2 ng/mL above nadir following radiation therapy or ≥1 ng/mL after radical prostatectomy, with or without postoperative radiation therapy. Patients in this trial were randomized 1:1:1 to combination enzalutamide + leuprolide, leuprolide monotherapy, or enzalutamide monotherapy. This trial met its primary endpoint of improved 5-year metastasis-free survival with the combination of enzalutamide + leuprolide (87.3% versus 71.4% for leuprolide alone; HR 0.42, p < 0.001). Similarly, enzalutamide monotherapy was associated with superior 5-year metastasis-free survival rates, compared to leuprolide monotherapy (80% versus 71%; HR 0.63, p = 0.005).²

However, the ‘elephant in the room’ is that patients in the EMBARK trial, who were enrolled between January 2015 and August 2018, were staged using conventional imaging, as opposed to prostate-specific membrane antigen (PSMA) positron emission tomography (PET), which has emerged as a standard of care imaging modality for biochemically recurrent patients, owing to its improved sensitivity for detecting metastatic disease in this setting.^3,4 As such, many experts in the field have suggested that there is a ‘discord’ between the study design of EMBARK and contemporary practice.

In this Center of Excellence article, we will discuss the results of the EMBARK trial within the context of contemporary PSMA PET imaging and discuss ongoing trials of biochemically recurrent M0 HSPC patients.

PSMA PET Findings in an ‘EMBARK-like’ Cohort

Had trial participants in EMBARK undergone a PSMA PET at study inclusion, what would a PSMA PET scan have shown? At ASCO 2023, Armstrong et al. presented the results of a post-hoc, retrospective analysis of four prospective studies of PSMA PET conducted at UCLA between 2016 and 2021 that included high-risk biochemically recurrent prostate cancer patients who would have met the EMBARK trial eligibility criteria. The study cohort included 183 patients, with a median time from primary therapy to PSMA PET of 39 months. The median serum PSA level at PSMA PET was 2.8 ng/mL, and the median PSADT was 3.6 months.

Overall, 85% of patients were PSMA PET positive, with an average of 3.9 lesions per case. Pelvic nodal disease was present in 56% of patients, and 30% had evidence of extra-pelvic nodal disease. Bone lesions were present in 26% of patients, and 4.4% of patients had visceral metastases:

Overall, 23% of patients had evidence of nodal-only disease (i.e., T_anyN₁M₀), 46% had distant metastases (T_anyN_anyM₁), 37% of patients had oligometastatic disease, and 9% had polymetastatic disease (i.e., >5 M1 lesions).⁵ A visual distribution of the metastatic breakdown is shown below:

Metastasis-Directed Therapy or Systemic Therapy Intensification for ‘EMBARK-like’ Patients

One of the proposed treatment paradigms for the contemporary management of an ‘EMBARK-like’ patient is obtaining a PSMA PET scan and targeting PET-avid lesions with metastasis-directed therapy (MDT), particularly for patients with evidence of oligometastases (i.e., ≤5 lesions), to maximize the systemic therapy-free interval. There are, however, important differences between the EMBARK cohort and the three major phase II trials of MDT in oligorecurrent hormone sensitive prostate cancer: STOMP, ORIOLE, and EXTEND.^6,7,8 The major difference is that patients in STOMP and ORIOLE had evidence of metastatic disease on non-PSMA PET imaging (STOMP: choline PET/CT; ORIOLE: conventional imaging [CT, MRI, and/or bone scan]), whereas those in EMBARK had no evidence of metastasis on conventional imaging.

It is important to note, however, that approximately 40% of patients of ‘EMBARK-like’ patients will have oligometastatic disease on a PSMA PET. There is evidence from the ORIOLE trial to support MDT targeting of all PSMA avid lesions. In this trial, pre-treatment ¹⁸F-DCFPyL-PET/CT was performed in all patients assigned to the MDT arm (n = 36), and the treating physicians and patients were blinded to the results of these scans. Sixteen patients (44%) had baseline PET-avid lesions that were not included in the MDT treatment fields and had significantly worse 6-month progression rates of 38% (95% CI 18.5–61.5%) compared to those without untreated lesions (5%; 95% CI 0–26.8%; 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).⁶

What about the use of MDT with systemic hormonal therapy? The phase II EXTEND trial demonstrated that the addition of MDT to 6 months of intermittent hormonal therapy significantly improved eugonadal progression-free survival (HR 0.32, p = 0.03). However, similar to the ORIOLE and STOMP, patients had evidence of metastatic disease, mostly identified on conventional imaging (75%). Additionally, approximately 90% of patients had a serum PSA level <2 ng/ml at study entry, whereas the median serum PSA level in EMBARK was 5–5.5 ng/ml. Notably, only 72% of the EXTEND trial patients had undergone definitive local therapy to the prostate, whereas all patients in EMBARK had undergone a radical prostatectomy and/or pelvic radiotherapy, with 50% having undergone both treatment modalities. As such, there are clear differences between the two study cohorts that limit trial comparisons and the generalizability of results and treatment approach used in EXTEND to EMBARK trial participants.

What about the use of MDT with androgen receptor pathway inhibitors? To date, there are no randomized trials comparing the added benefit of combining one modality with the other (ARTO trial of abiraterone +/- stereotactic body radiotherapy [SBRT] was in the castrate-resistant setting) in this disease space.⁹ The only published trial of combination MDT with androgen receptor pathway inhibitors in oligorecurrent metastatic prostate cancer patients is the phase II SATURN trial, in which patients received six months of leuprolide + abiraterone acetate/prednisone + apalutamide and SBRT to all metastases, with or without radiotherapy directed to the prostate bed and pelvic lymph nodes, after the first month of systemic therapy. Overall, 50% of patients maintained a PSA <0.05 ng/mL six months after testosterone recovery (primary endpoint), and the median eugonodal progression-free survival was 11.4 months.¹⁰

One pragmatic approach to treating an ‘EMBARK-like’ patient that has PSMA PET findings of metastatic disease (ie. conventional imaging negative, PSMA PET positive for metastatic disease) is to treat these patients with enzalutamide + leuprolide, rather than enzalutamide monotherapy or leuprolide monotherapy. The rationale for such an approach is that these patients are more “ENZAMET/ARCHES-like” patients, where there is a proven therapeutic benefit of enzalutamide + ADT versus ADT alone in the mHSPC setting.^11,12

In summary, the only available level one evidence to inform the treatment of high-risk, biochemically recurrent M0 HSPC patients staged with conventional imaging comes from the EMBARK trial, where both enzalutamide combination therapy with leuprolide and enzalutamide monotherapy have demonstrated metastasis-free survival benefits. Future randomized trials in this space may provide further answers to the question of optimal management of these patients who have PSMA PET positive disease. For the time being, however, similar to the mHSPC treatment paradigm which relies on conventional imaging volume findings to dictate treatment recommendations, high-risk, biochemically recurrent patients with conventional imaging-defined M0 HSPC should be recommended to receive systemic therapy with androgen receptor pathway inhibitors.

Ongoing Trials Utilizing PSMA PET in the High-Risk, Biochemically Recurrent M0 HSPC Space

ARASTEP (NCT05794906) is an ongoing randomized, phase III, double-blind, placebo-controlled trial of prostate cancer patients with high-risk biochemical recurrence, defined by a PSADT <12 months with PSA ≥ 0.2 ng/mL after primary radical prostatectomy (+/- adjuvant radiotherapy/salvage radiotherapy) or PSA ≥2 ng/mL above nadir after primary radiotherapy only, ≥1 PSMA PET/CT-positive lesion of prostate cancer without visible lesions on conventional imaging, and serum testosterone >150 ng/dL.

Approximately 750 patients from 184 sites worldwide will be randomized to oral darolutamide 600 mg twice daily or placebo, both with ADT, for 24 months, unless there is earlier evidence of disease progression, unacceptable toxicity, or any other withdrawal criteria are met. Of note, patients will suspend treatment after 24 months if serum PSA levels remain undetectable (i.e., <0.2 ng/mL). Patients whose PSA values remain detectable (i.e., ≥0.2 ng/mL) will continue with the study treatment until PSMA PET/CT progression. The trial design for ARASTEP is as follows:

The primary study endpoint is radiographic progression-free survival by PSMA PET/CT, assessed by a blinded independent central review. Key secondary endpoints include:

• Metastasis-free survival by blinded independent central review
• Time to CRPC
• Overall survival
• Quality of life
• Safety

INDICATE (ECOG-ACRIN EA8191; NCT04423211) is a phase III trial that aims to evaluate the following in post-radical prostatectomy biochemically recurrent patients without evidence of metastases on conventional imaging:¹³

1. Whether the addition of apalutamide to standard salvage radiotherapy plus short-term ADT improves survival in patients without extra-pelvic PET-detected lesions
2. Whether the addition of MDT to the treatment intensification combination of salvage radiotherapy, short-term ADT, and apalutamide improves survival in patients with PET-detected lesions outside the pelvis

Eligible patients are those with biochemical recurrence post-radical prostatectomy, defined by a serum PSA level >0.5 ng/ml or >0.2 ng/ml, if detected within 12 months of the radical prostatectomy, and no evidence of extra-pelvic metastases on conventional imaging, who are candidates for standard of care salvage therapy (salvage radiotherapy to the prostate bed and pelvic node with concurrent short-term ADT). Of note, if a patient has a detectable PSA (≥0.01 ng/ml) at any time after radical prostatectomy and has a baseline PET that is positive for ≥1 lesion in any location, there is no minimum PSA requirement.

All patients will undergo baseline PET using one of the three FDA-approved tracers, at which point patients will be assigned to either Cohort 1 (PET negative for extra-pelvic metastases) or Cohort 2 (PET positive for extra-pelvic metastases). The study design is as follows:

Patients in Cohort 1 (PET negative) will be randomized to either:

• Arm A: Salvage external beam radiotherapy (EBRT) + short-term ADT (leuprolide or goserelin) OR
• Arm B: Salvage EBRT + short-term ADT + apalutamide

Patients in Cohort 2 (PET positive for extra-pelvic metastases) will be randomized to either:

• Arm C: Salvage EBRT + short-term ADT + apalutamide OR
• Arm D: Salvage EBRT + short-term ADT + apalutamide + MDT (SBRT)

The primary endpoint in both cohorts is progression-free survival, defined as time from randomization to radiographic progression on conventional imaging, symptomatic disease progression, or death, whichever occurs first. Secondary endpoints include overall and event-free survival, toxicity, PET progression, and quality of life. The study accrual start date was October 2022, with an estimated primary completion date of December 2027.

Conclusions

Based on the current body of evidence, high-risk, biochemically recurrent patients without evidence of metastases on conventional imaging should be strongly considered for systemic therapy with enzalutamide combination therapy with leuprolide or monotherapy. Despite PSMA PET detecting extra-pelvic metastases in almost 50% of such patients, there is no high-level evidence, to date, to support the routine utilization of PSMA PET findings to direct treatment with SBRT. Ongoing trials will help address important remaining questions in this disease space, namely the value/utility of PSMA PET in patients with negative conventional imaging findings and the added benefit of PSMA PET-directed SBRT to systemic therapy intensification with androgen receptor pathway inhibitors in patients with PSMA PET/conventional imaging discordant findings.

Published November 2024 

Introduction

Introduction

At the ESMO 2024 annual meeting in Barcelona, Spain, the results of numerous practice-changing trials were presented, including those from three highly-anticipated clinical trials in the advanced prostate cancer space:

ESMO 2024 Quick Take Insights: A Focus on PEACE-3

The ESMO 2024 annual meeting in Barcelona, Spain, featured many practice-changing trials and hypothesis-generating data in genitourinary cancer. One of the most highly anticipated trials in the metastatic castration-resistant prostate cancer (mCRPC) disease space was the phase III PEACE-3 trial – the focus of this ESMO 2024 Quick Take Insights.

ESMO 2024 Quick Take Insights: A Focus on SPLASH

The ESMO 2024 annual meeting in Barcelona, Spain, featured many practice-changing trials and hypothesis-generating data in genitourinary cancer. One of the most highly anticipated trials in the metastatic castration-resistant prostate cancer (mCRPC) disease space was the phase III SPLASH trial – the focus of this ESMO 2024 Quick Take Insights.

Introduction

EMBARK

Safety

• Physical well-being score: Significantly worse time to confirmed clinically meaningful deterioration of physical well-being score for both enzalutamide combination and monotherapy arms (leuprolide: 50 months; enzalutamide combination/monotherapy: 25–28 months). These scores likely reflect the higher incidence of fatigue with enzalutamide combination (43%) or monotherapy (47%), versus leuprolide-only therapy (33%).
• Prostate cancer subscale score and advanced prostate symptom index: Worse for enzalutamide monotherapy patients
• Social/family, emotional, and functional well-being and prostate cancer pain FACT-P domains: No differences between the arms
• Sexual function: Deteriorates in all three arms. Significantly longer time to confirmed clinically meaningful deterioration of composite sexual activity with enzalutamide monotherapy (5.6 versus 3 months). Patients treated with enzalutamide monotherapy reported superior sexual interest and activity and had higher satisfaction with their sexual life and ability to achieve and maintain erections. Enzalutamide combination therapy patients had significantly worse ability to achieve and maintain erections.
• Hormonal treatment-related symptoms: Enzalutamide combination patients had a significantly worse time to confirmed clinically meaningful deterioration in hormonal treatment-related symptoms
• Notable adverse events:
  • Hot flashes: More common in the enzalutamide + leuprolide and leuprolide-only arms (57–69% versus 22% for enzalutamide monotherapy)
  • Gynecomastia nipple pain, and breast tenderness: More common with enzalutamide monotherapy
    • Gynecomastia: 45% versus 8–9%
    • Nipple pain: 15% versus 1–3%
    • Breast tenderness: 14% versus 1%

Summary and Take-Home Messages

Introduction

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

The treatment landscape of metastatic castrate-resistant prostate cancer (mCRPC) has long been dominated by androgen receptor pathway inhibitors (ARPIs) and chemotherapeutic agents. There are currently, however, two radioligands that are United States Food and Drug Administration (FDA)-approved for the treatment of mCRPC patients: