ESMO 2023: Invited Discussant: Final Results of RADICALS RT & Interim Results from a Phase 1 Study of AMG 509 in Metastatic Castration Resistant Prostate Cancer (mCRPC)

(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a discussant presentation by Dr. Shahneen Sandhu. For this discussant, Dr. Sandhu assessed the abstract “Timing of Radiotherapy After Radical Prostatectomy: Final Results of RADICALS RT Randomized Controlled Trial” by Dr. Noel Clarke, and abstract “Interim Results from a Phase 1 Study of AMG 509 (xaluritamig), a STEAP1 x CD3 XmAb 2+1 Immune Therapy, in Patients with mCRPC” by Dr. William Kelly.

Based on the RADICALS-RT,¹ GETUG-AFU 17,² and RAVES trials,³ in addition to the ARTISTIC meta-analysis,⁴ we have high quality data to assess adjuvant versus early salvage radiotherapy for men with high risk disease after radical prostatectomy:
From the ARTISTIC meta-analysis, there are no discernable differences in primary or secondary outcomes between adjuvant and salvage radiotherapy:

As such, we are able to potentially mitigate morbidity with early salvage rather than adjuvant radiotherapy. Dr. Sandhu notes that perhaps we can personalize therapy based on imaging, specifically using PSMA PET to help tailor radiation fields when disease is detected. Additionally, the RTOG 0534/SPPORT trial was an international, multicenter randomized trial of 1,792 patients who previously underwent a radical prostatectomy and have evidence of residual disease (i.e. persistent PSA post-operatively) or a rising PSA of between 0.1 and 2.0 ng/ml.⁵ Patients who had previously underwent a lymphadenectomy were eligible, given that they had no clinical or pathologic evidence of nodal involvement. Patients were equally randomized into 1one of three arms:

1. Group 1: Prostate-bed radiotherapy (64.8 – 70.2 Gy; 1.8 Gy/fraction)
2. Group 2: Prostate-bed radiotherapy + short-term ADT (4-6 months)
3. Group 3: Prostate-bed radiotherapy + short-term ADT + pelvic nodal radiotherapy

The primary outcome was freedom from progression, defined as biochemical failure according to the Phoenix criteria (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. At a median follow-up of 8.2 years in survivors, the 5-year freed from progression rates were 70.9% (95% CI: 67.0 – 74.9) in group 1, 81.3% (78.0 – 84.6) in group 2, and 87.4% (84.7 – 90.2) in group 3:

As expected, there was no difference in overall survival among these 3 arms in the SPPORT trial:
Acute grade 2 or worse adverse events were significantly higher in group 3 (44%), followed by group 2 (36%) and group 1 (18%; p for all < 0.0001). However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, except for later grade 2 or worse blood or bone marrow events in group 3 versus group 2 (p = 0.0060).

 With the increased utilization of molecular imaging (ie with ¹⁸F-fluciclovine and PSMA PET/CT) to guide treatment decision making and planning in the biochemical recurrent disease space, the EMPIRE-1 trial sought to evaluate whether ¹⁸F-fluciclovine improves cancer control compared to conventional imaging (bone scan + CT/MRI) alone for salvage post-prostatectomy radiotherapy [6]. This was a single center, open label, phase 2/3 trial of post-prostatectomy patients with a detectable post-operative PSA and negative conventional imaging. These patients were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus ¹⁸F-fluciclovine-PET/CT. In the ¹⁸F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary study outcome was 3-year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy. Over a median follow-up of 3.52 years, the 3-year event-free survival was significantly improved in the ¹⁸F-fluciclovine arm: 75.5% versus 63.0% (difference 12.5; 95% CI: 4.3–20.8; p = 0.0028), which was confirmed on adjust analysis (HR: 2.04, 95% CI: 1.06 – 3.93, p = 0.0327):

The toxicity profile tended to favor those in the ¹⁸F-fluciclovine arm, although results were non-significantly different.

Dr. Sandhu notes that there are several prospective trials that are incorporating PSMA PET scans:
So, is there a subset of post-operative patients that may benefit from treatment intensification, including adjuvant radiotherapy? From the NCCN guidelines, Dr. Sandhu notes that ArteraAI Prostate Test (biochemical recurrence, distant metastasis, and prostate cancer specific mortality) and Decipher (distant metastasis) are risk stratification tools to prognosticate certain endpoints. Dr. Spratt and colleagues have previously demonstrated that a digital pathology-derived AI biomarker may be used to predict short-term ADT benefits for intermediate risk patients.⁷ Intermediate risk patients who were biomarker negative did not benefit from short-term ADT. Conversely, those with a positive biomarker status had significantly decreased distant metastases rates when short-term ADT was added to radiotherapy (HR: 0.33, p<0.001): At ASCO 2023, Dr. Andrew Armstrong presented results of a pooled analysis of multiple phase III NRG/RTOG trials aimed at developing and subsequently validating an AI-derived digital pathology-based biomarker to predict the benefit of long-term ADT addition to radiotherapy in men with localized, high-risk prostate cancer. The validation analysis in the NRG/RTOG 9202 cohort demonstrated that the ArteraAI Prostate Test biomarker was a significant predictor of the utility of long-term ADT use in this cohort (interaction p=0.04). As demonstrated below, patients in the biomarker negative group (n = 407) derived no benefit from long-term ADT use, compared to short-term ADT use (HR 1.06, 95% CI 0.61 – 1.84). Conversely, patients in the biomarker positive group had significant improvements in the distant metastasis rates with long-term ADT (HR 0.55, 95% CI 0.41 – 0.73). Accordingly, approximately 1/3 of men with high-risk prostate cancer could have safely avoided long-term ADT based on the results of this predictive biomarker analysis:

Dr. Sandhu then highlighted the PROSTATE-IQ trial, which is using ArteraAI Prostate Test post-prostatectomy scores to tailor the intensity of androgen axis therapy:

For the discussion between adjuvant or early salvage radiotherapy, Dr. Sandhu offered the following take home messages:

• Overall, there is no benefit from adjuvant radiotherapy compared with early salvage radiotherapy
• Early salvage radiotherapy spares the vast majority of patients from having radiotherapy
• The morbidity from early salvage radiotherapy is low
• PSMA PET can be used to define the extent of disease and potentially prognosticate and be used to tailor radiotherapy fields
• Potentially better molecular tools beyond clinicopathological features, such as ArteraAI Prostate Test or Decipher scores, could be integrated into prospective post-operative trials to better understand who needs treatment intensification and de-intensification

Dr. Sandhu then discussed the interim results of xaluritamig in patients with mCRPC. She notes that STEAP1 is part of a family of metalloproteinases involved in iron and copper homeostasis. Additionally, it is a cell surface antigen that is highly expressed in prostate cancer and other cancers, playing a role in regulating cell proliferation and apoptosis, attenuating oxidative stress, and modeling the transferrin cycle. STEAP1 overexpression promotes tumor growth, with limited expression in normal tissue making it an attractive therapeutic target for antibody drug conjugates, CAR-T and BiTES.

This was a phase 1 trial of mCRPC patients refractory to prior novel hormonal therapy and 1–2 taxane regimens, ECOG 0–1, and adequate organ function. Xaluritamig was administered as an IV weekly or every 2 weeks with various dose levels/schedules. The study objectives were to evaluate safety, tolerability, antitumor activity, pharmacokinetics, and determine the maximum tolerated dose and recommended phase 2 dose. The trial design is as follows:
As of March 23, 2023, 97 patients in 15 dose levels received ≥1 dose of xaluritamig. The median age was 67 (range: 40–86) years and 67 patients (69.1%) had received > three prior lines of therapy, with a median of four prior lines of therapy. The dose exploration with step-dosing and prophylactic regimen to determine the maximum tolerated dose is as follows:
The maximum tolerated dose was identified as 1.5 mg IV weekly (3-step, D1 0.1 mg / D8 0.3 mg / D15 1.0 mg / D22+ 1.5 mg). PSA50 (≥ 50% PSA decline) responses occurred in 43 patients (49%) and PSA90 (≥ 90% PSA decline) in 24 patients (28%). PSA responses were more frequent at higher dose levels (DL7b–15) than in lower dose levels (DL1–7a). Overall, RECIST responses included 16 (24%) confirmed partial responses and 32 (48%) with stable disease. At higher dose levels, 15 patients (41%) had confirmed partial responses, and 14 (38%) stable disease:
Treatment emergent adverse events were reported in 100% of patients (grade ≥3, 76%), and 97% reported treatment-related adverse events (grade ≥3, 55%). Treatment-related adverse events leading to discontinuation occurred in 19% of patients.:
The most common adverse events were cytokine release syndrome (72.2%), fatigue (52.6%), anemia (45.4%), pyrexia (40.2%), and myalgia (39.2%). Cytokine release syndrome was primarily grade 1 or 2, one event being grade 3 (no grade 4/5 cytokine release syndrome events):

There were 19 patients from high dose cohorts (n = 52) that remained on treatment at data cutoff, and of those 13 patients remained on treatment for > 6 months. The median duration of response was 9.2 months (range: 1.9+ to 17.7+). Dr. Sandhu notes the following reasons why T-cell engagers are attractive in prostate cancer:

• Prostate cancer is a highly immune suppressive tumor, thus we will need novel strategies to engage the immune system
• There is an ease of “off the shelf” as opposed to CAR-Ts
• There is no need for chemotherapy preconditioning
• They engage all cytotoxic T cells, including CD8, CD4, NK cells, etc
• There is no need for co-stimulation
• They are independent of peptide MHC/TCR recognition
• They do not require high antigen expression for activity
• There is evidence of very robust single cell activity in the clinic, specifically for hematology malignancies
• Response often very rapid, with a median time to response of weeks

However, there are several challenges with BiTEs in solid tumors:

• Dose dependent efficacy with a very narrow therapeutic index, which is dependent on tumor antigen specificity, thus the cleaner the better
• On target toxicity, target expression on normal tissue (ie. neurotoxicity)
• Off target toxicity, related to the mechanism of action and T cell activation, resulting in cytokine release syndrome and liver toxicity
• Cytokine release syndrome in response to BiTE is the result of T cell binding, engagement and is often seen in the first doses and can be mitigated with step up dosing
• Synapses between the BiTE and T cells are very large, which is good for T cell activation but could also lead to rapid T cell exhaustion
• Clinical aspects for the treating team and the patient, including resourcing and hospitalization
• Upskilling in terms of managing toxicity

Despite these encouraging results presented, cautious optimism is needed:

Dr. Sandhu concluded her discussant presentation of this abstract assessing xaluritamig in mCRPC with the following take-home points:

• Cancer immunotherapies have offered limited efficacy in treating mCRPC
• BiTEs are a novel class of immunotherapy that target both a specific cancer antigen and CD3 to enhance T cell anti-tumor activity
• Xaluritamig is the first clinical T-cell engager targeting STEAP1
• The preliminary efficacy data is promising
• Many new BiTEs are in development for mCRPC and there is a need to understand how we position these agents in the treatment paradigm of mCRPC
• We need to improve the toxicity profile of these agents for ease of delivery, otherwise, we are unlikely to broadly have uptake in the community
• Peptide MHC-specific BiTE (ie. tebentafusp) will allow access to an enlarged target space and may activate T cells in a more physiological fashion
• The role of combinations with costimulatory signals, cytokines, and immune checkpoint inhibitors may increase the response rates and will need to be carefully interrogated given likely additional toxicity in elderly patients

Presented by: Shahneen K. Sandhu, MD, Peter MacCallum Cancer Centre, Melbourne, Australia

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.

References:

1. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): A randomized, controlled phase 3 trial. Lancet 2020;396(10260):1413-1421.
2. Sargos P, Chabaud S, Latorzeff I, et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): A randomized, phase 3 trial. Lancet Oncol 2020;21(10):1341-1352.
3. Kneebone A, Fraser-Browne C, Duchesne GM, et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): A randomized, controlled, phase 3, non-inferiority trial. Lancet Oncol. 2020;21(10):1331-1340
4. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localized and locally advanced prostate cancer: A prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020 Oct 31;396(10260):1422-1431.
5. Pollack A, Karrison TG, Balogh AG, et al. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): An international, multicentre, randomized phase 3 trial. Lancet. 2022 May 14;399(10338):1886-1901.
6. Jani AB, Schreibmann E, Goyal S, et al. 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): A single centre, open-label, phase 2/3 randomized controlled trial. Lancet. 2021 May 22;397(10288):1895-1904.
7. Spratt DE, Tang S, Sun Y, et al. Artificial Intelligence Predictive Model for Hormone Therapy Use in Prostate Cancer. NEJM Evid 2023;2(8).