(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer therapy session. Dr. Fuad Novruzov presented the results of a prospective phase 3 randomized study from Azerbaijan evaluating ²²⁵Ac-PSMA + ¹⁷⁷Lu-PSMA tandem therapy for metastatic castration-resistant prostate cancer (mCRPC).

e(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer therapy session. Vishnu Murthy presented the results of a US expanded access program evaluating the efficacy and toxicity of ¹⁷⁷Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC) in a real-world setting and compared these results to those from the phase 3 VISION trial.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer therapy session. Dr. Meryam Losee presented the results of a study evaluating the effect of bone marrow disease on hematologic toxicity and PSA response to ¹⁷⁷Lu-PSMA-617 therapy. 

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer therapy session. Dr. Benjapa Khiewvan presented the first Thai experience with Lu-177-PSMA-I&T treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC).

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) tumor board session. Dr. Oliver Sartor discussed whether earlier use of PSMA RLT in earlier settings is of clinical benefit.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer therapy session. Dr. Oliver Sartor presented the updated results of PSMAfore, a phase 3 trial of [¹⁷⁷Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC).

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer therapy session. Dr. Josef Zahner presented the first dosimetry results of a study evaluating the influence of androgen receptor pathway inhibitors (ARPIs) on absorbed doses in metastatic castrate-resistant prostate cancer (mCRPC) patients undergoing ¹⁷⁷Lu-PSMA-617 therapy.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) tumor board session. Dr. Michael Hofman discussed patient eligibility for RLT, highlighting the patient populations most likely to benefit from these targeted therapies.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer imaging session. Dr. Joseph Frankl presented the results of an analysis of primary lesion ⁶⁸Ga-PSMA-11 total lesion activity as a highly sensitive predictor, with a concurrent high negative predictive value, of advanced-stage disease for the initial staging of patients with moderate to high-risk prostate cancer.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer imaging session. Dr. Gary Cook discussed the associations between clinical risk factors, metastases, and imaging parameters for patients with high-risk prostate cancer undergoing baseline staging with ⁶⁸Ga-PSMA-11 PET/CT.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer imaging session. Dr. Francisco Osvaldo García-Pérez presented an analysis of the use of ¹⁸F-PSMA-1007 PET /CT for the evaluation of atypical patterns of spread in ISUP Grade Group 5 prostate cancer.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer imaging session. Dr. Rajender Kumar presented the results of a study evaluating percutaneous trans-gluteal Ga-68 PSMA PET/CT guided prostate biopsy in men with equivocal multiparametric MRI findings (i.e., PIRADS≤3 lesions).

The ESMO/EAU guidelines currently recommend performing a multiparametric MRI (mpMRI) in men with suspected prostate cancer prior to a prostate biopsy. However, a significant proportion of men with equivocal mpMRI findings (i.e, PIRADS ≤3) may harbor clinically significant disease, which may be missed if biopsy is limited to patients with PIRADS 4–5 disease.

There has been increased interest in evaluating ⁶⁸Ga PSMA PET/CT in the primary diagnostic setting, particularly among men with a prior negative biopsy. In this prospective study, Dr. Kumar and colleagues evaluated the value of ⁶⁸Ga PSMA-PET/CT-guided prostate biopsy in participants with PIRADS ≤3 lesions.

In this prospective study, participants meeting all of the following criteria were recruited and underwent whole-body ⁶⁸Ga PSMA-PET/CT imaging:

• Lower urinary tract symptoms/abnormal digital rectal examination
• Elevated serum PSA >4 ng/ml
• Equivocal findings on mpMRI (i.e., PIRADS ≤3 lesions)

Exclusion criteria were as follows:

• Platelet counts <80,000
• Acute prostatitis or positive urine culture
• Metallic stent in situ

Two qualified nuclear medicine physicians reviewed the PET/CT imaging. A focal PSMA avid lesion in the prostate was considered PET-positive. Non-avid or heterogenous PSMA expression was considered PET negative and patients did not undergo a biopsy. The PET-positive patients underwent PET-guided prostatic biopsies through the trans-gluteal approach using an automated robotic arm to guide needle placement for prostatic lesion targeting. Society of Interventional Radiology consensus guidelines were followed for the procedures. Data regarding the location of tracer uptake in the prostate, SUV_max, visual analysis score (VAS) for pain, procedure-related complications, and histopathology with ISUP grade were collected. All patients had urine cultures performed 48 hours following the biopsy procedure.

A total of 50 participants were prospectively enrolled. The mean PSA level at enrollment was 12 ng/ml (range 4.3 to 19.7 ng/ml). Prostatic PSMA avid lesions were detected in 21/50 (42%) study participants. The mean SUVmax of the PET-positive lesions was 19.1 +/- 13.9. All PET-positive patients underwent PET/CT-guided prostatic biopsies, which were technically feasible in all 21 patients and all specimens retrieved were adequate for pathological analysis. Of note, one patient had a non-representative sample and required a repeat biopsy. The overall diagnostic yield was 100%. Intermediate-risk prostate cancer was diagnosed in 10 (20%) patients. Eleven (22%) patients were diagnosed with low-risk prostate cancer. 

The mean VAS was 2.5 ±1.7 (> 5 in three). Minor complications (gluteal pains and hematuria) were noted in five patients. None of the patients required hospital admission. None of the patients developed fever or post-procedural infection. None of the PET-negative participants with a PIRADS ≤3 lesion has yet to be diagnosed with prostate cancer on follow-up.

Dr. Kumar concluded as follows:

• The present study demonstrates that many clinically significant prostate cancer lesions are missed when prostate biopsy is limited to patients with PIRAD >3 lesions on mpMRI.
• PSMA PET/CT-guided biopsy is a promising approach to diagnose prostate cancer in participants with equivocal mpMRI findings and a clinical suspicion for prostate cancer.
• This study suggests that a biopsy can be avoided for patients with PIRADS ≤3 lesions and no PSMA avid lesion, with none diagnosed with prostate cancer during the study follow-up period.

Presented by: Rajender Kumar, Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) tumor board session. Dr. Louise Emmett discussed the rationale for and against combining RLT with other agents in treating prostate cancer patients.

To date, there have been two major trials of ¹⁷⁷Lu-PSMA-617 for metastatic castrate-resistant prostate cancer (mCRPC): VISION and TheraP.^1,2

VISION is an international, open-label, phase 3 trial that evaluated ¹⁷⁷Lu-PSMA-617 in mCRPC patients previously treated with an androgen receptor pathway inhibitor (ARPI) and 1-2 taxane regimens and who had PSMA-positive ⁶⁸Ga-PSMA-PET/CT scans. Between June 2018 and October 2019, 831 patients were randomly assigned in a 2:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. At a median follow-up of 20.9 months, ¹⁷⁷Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard of care, both radiographic progression-free survival (rPFS; median: 8.7 versus 3.4 months; HR: 0.40, p<0.001) and overall survival (median: 15.3 versus 11.3 months; HR: 0.62; 95% CI: 0.52 to 0.74, p<0.001).

Patient reported outcomes as evaluated by the FACT-P and Brief Pain Inventory (BPI) scores favored the ¹⁷⁷Lu-PSMA-617 arm with delays in time to worsening of 7.3 and 11.4 months, respectively.

While a higher rate of high-grade (grade 3-5) treatment-emergent adverse events was observed with ¹⁷⁷Lu-PSMA-617 (28.4% versus 3.9%) at the time of initial reporting, overall therapy was well tolerated. It bears note that treatment exposure was more than three times longer in the ¹⁷⁷Lu-PSMA-617 group than in the control group.

TheraP was an open label, phase II trial of 200 mCRPC men who were randomized to either ¹⁷⁷Lu-PSMA-617 or cabazitaxel. To screen into the study, all men had both ⁶⁸Ga-PSMA-11 and ¹⁸F-FDG PET/CT and were required to have high PSMA-expression (≥1 site with SUVmax ≥20) and no sites of FDG-positive/PSMA-negative disease. All patients had progressive disease with rising PSA ≥20 ng/mL after docetaxel and 91% had received prior enzalutamide or abiraterone. 200 patients were randomized 1:1 to ¹⁷⁷Lu-PSMA-617 6-8 GBq every 6 weeks for up to 6 cycles of therapy or cabazitaxel 20 mg/m² every three weeks for up to 10 cycles.

The most recent update of TheraP was presented at ASCO 2022 after a median follow-up of 36 months. Progression-free survival favored LuPSMA (HR: 0.62, 95% CI: 0.45 – 0.85). There was however no significant difference in overall survival between the two arms (restricted mean survival time: 19.1 months in ¹⁷⁷Lu-PSMA-617 arm versus 19.6 months in cabazitaxel arm, 95% CI for difference: -3.7 - +2.7).³

An exploratory analysis of the varying effects of ¹⁷⁷Lu-PSMA-617 on overall survival in TheraP versus VISION was presented at ASCO 2023 – why were the hazard ratios (HRs) for ¹⁷⁷Lu-PSMA-617 significantly different in these two trials (VISION: 0.62 versus TheraP: 0.97). First, it appears that the choice of comparator arm makes a significant difference. Patients in the cabazitaxel comparator arm of TheraP had a significantly longer overall survival compared to those in the standard of care arm in the VISION trial (HR: 0.57, 95% CI: 0.43 – 0.75). Overall survival was similar in the ¹⁷⁷Lu-PSMA-617 groups of VISION and TheraP (HR: 0.92, 95% CI: 0.70 – 1.19). No significant differences in overall survival between the ¹⁷⁷Lu-PSMA-617 and cabazitaxel groups of TheraP were apparent using counterfactual analyses assuming crossovers had not occurred. As such, the investigators concluded that the difference in observed effects of ¹⁷⁷Lu-PSMA-617 on overall survival in TheraP and VISION are better explained by the use of different comparator treatments in their control groups than by crossovers in TheraP from cabazitaxel to ¹⁷⁷Lu-PSMA-617, or ¹⁷⁷Lu-PSMA-617 to cabazitaxel.

A rationale for considering Lu-PSMA combination therapies is that patients with evidence of disease visual heterogeneity on ⁶⁸Ga-PSMA-11 PET/CT have worse disease outcomes with radioligand therapy. It is important to consider the likelihood of treatment benefit in candidate patients. Recently, Dr. Emmet’s group developed a 4-category score incorporating both heterogeneity and intensity of tumors (HIT) using a combination of heterogeneity and intensity:³

• Category 1: SUVmax <15
• Category 2: SUVmax 15-79 with heterogeneous intensity
• Category 3: SUVmax 15-79 with homogenous intensity
• Category 4: SUVmax ≥80

As demonstrated in the Kaplan Meier curve below, patients in the higher category groups had superior outcomes with Lu-PSMA therapy. The median PSA progression-free survivals were:

• Category 1: 1 month
• Category 2: 4.1 month
• Category 3: 6.0 month
• Category 4: 8.5 month 

As such, patients with heterogenous PSMA expression may be ideal candidates for combination approaches, that would ideally achieve all of the following:

• Combining PSMA-targeting treatment with an agent that has a complementary effect that targets cells that do not express PSMA.
• Combine PSMA-targeting treatment with an agent likely to enhance PSMA expression.
• Combine PSMA-targeting treatment with an agent likely to enhance radiation sensitivity.
• Not significantly increasing toxicity

One example of a RLT combinatory approach that allows for the targeting of cells without PSMA expression is the combination of ¹⁷⁷Lu-PSMA-617 + enzalutamide. There is a close relationship between the androgen and PSMA receptors, with upregulation of PSMA expression in response to androgen blockade observed in mCRPC. This increased PSMA expression is associated with poor survival in CRPC patients receiving ARPIs. Increased PSMA expression increases dsDNA breaks and cell death with Lu-PSMA therapy, increasing the depth of treatment response. This reduces/eliminates the high PSMA expressing clonal population, leaving a low PSMA expression clonal population more likely to respond to ARPIs. The ENZA-p trial investigators hypothesized that using both treatments together may lead to potentially deeper and longer patient responses, compared to ARPI monotherapy.

ENZA-p (ANZUP 1901) is an open label, randomized phase 2 trial across 15 centers in Australia of 162 mCRPC patients who had not previously received a taxane or an ARPI in the mCRPC setting, had ⁶⁸Ga-PSMA-PET/CT-positive disease, and ≥2 risk factors for early progression on enzalutamide. These patients underwent 1:1 randomization to enzalutamide +/- ¹⁷⁷Lu-PSMA-617.

Of 220 screened patients, 160 met the eligibility criteria and were randomized (enzalutamide + Lu-PSMA, n=83; enzalutamide, n=79). The PSMA PET imaging screen failure rate was 18%. In the combination arm, 81% of patients received all 4 doses of Lu-PSMA. The median follow-up was 20 months.

This trial met its primary endpoint, with the addition of ¹⁷⁷Lu-PSMA-617 to enzalutamide improving PSA progression-free survival from 7.8 to 13 months (HR: 0.43, 95% CI: 0.29 – 0.63, p<0.001). rPFS (data maturity: 60%) also favored the combination arm (median: 16 versus 12 months; HR: 0.67, 95% CI: 0.44 – 1.01).

A PSA50 response was observed in 93% of patients in the Lu-PSMA + enzalutamide arm, compared to 68% of enzalutamide-treated patients. The corresponding PSA90 responses were 78% and 37%, respectively.⁴

In the metastatic hormone-sensitive setting, the combination of Lu-PSMA and an ARPI is being evaluated in PSMAddition, summarized below. This is a phase 3 trial of ¹⁷⁷Lu-PSMA-617 + standard of care versus standard of care alone in patients with mHSPC (n=1,226). The study design is illustrated below. The primary study endpoint is rPFS, with crossover permitted at radiographic progression. Overall survival is a key secondary endpoint. Recruitment for this trial was completed in 2023, with an estimated study completion date of February 2026.

The combination of ¹⁷⁷Lu-PSMA-617 and cabazitaxel has been evaluated in the phase I/II LuCAB trial. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of ¹⁷⁷Lu-PSMA-617, while also treating any PSMA-negative disease. Additionally, systemic chemotherapy may effectively treat micrometastatic disease that may not be targeted by the beta emitter, ¹⁷⁷Lu-PSMA-617. LuCAB is a single arm phase I/II trial is evaluating the combination of ¹⁷⁷Lu-PSMA-617 plus cabazitaxel in mCRPC patients with disease progression following prior ARPI and docetaxel exposure and evidence of PSMA-positive disease on PSMA-PET/CT (SUVmax ≥15). The target sample size is 32 – 38 patients. Up to 6 doses of ¹⁷⁷Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m² - 20mg/m²), on Day 2 and Day 23 of each 6-week cycle:

The primary objective is to establish the maximum tolerated dose of cabazitaxel and [¹⁷⁷Lu-PSMA-617. Secondary objectives include:

• Measuring the frequency and severity of adverse events
• Assessment of efficacy through PSA 50% response rate
• Radiographic and PSA progression-free survival
• Overall survival
• Objective tumor response rate
• Evaluation of pain and health-related quality of life over the first 12 months

As of January 2023, five patients have been enrolled in the study, with preliminary results expected in the upcoming few years.⁵

What about combinations to enhance PSMA expression and thus potentially improve the efficacy of radioligand therapy? A screen of 147 anticancer agents demonstrated that the topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, upregulated PSMA protein expression in castration-resistant LNCaP95 cells. Additionally, ionizing radiation also upregulated PSMA protein expression in a dose-dependent fashion.⁶

What about combining PSMA targeting treatment with an agent likely to enhance radiation sensitivity/cell death? ¹⁷⁷Lu-PSMA-617 delivers significant Beta radiation to PSMA-expressing tumors, primarily causing single strand DNA breaks, which are typically repaired by PARP-dependent pathways. Blocking PARP could result in the conversion of DNA single strand breaks to lethal double strand breaks via replication fork collapse. In the LuPARP trial, the investigators hypothesized that the addition of olaparib could promote the radiosensitization of ¹⁷⁷Lu-PSMA-617, resulting in DNA damage intensification, and thus improved efficacy.

In LuPARP, 48 patients with mCRPC in the post-ARPI/docetaxel setting and PSMA expression (SUVmax 15 at a site of disease, and SUVmax ≥ 10 at other measurable sites) without discordant FDG positive/PSMA negative disease, received the combination of ¹⁷⁷Lu-PSMA-617 + olaparib in in two stages: dose-escalation (standard 3+3 design) and dose-expansion at the recommended phase 2 dose (RP2D). In this phase 1 trial, ¹⁷⁷Lu-PSMA-617 was administered at a dose of 7.4 GBq 6 weekly for 6 cycles. Olaparib was concurrently administered at a dose of 50 to 300 mg twice daily on days 2 to 15, -4 to 14, or -4 to 18 of each 6-week cycle. No dose-limiting toxicities were reported across the dose levels. There were no grade 4 adverse events. One treatment-related serious adverse event occurred (febrile neutropenia). From an efficacy standpoint, the PSA50 and PSA90 response rates in the overall cohort were 66% and 44%, respectively. The objective response rate by RECIST v1.1 criteria was 78%. How do these results compare to those from TheraP and VISION? The PSA50 responses from this trial were identical to those from TheraP (66%) and higher than that in VISION (46%). The PSA90 response of 44% in LuPARP was slightly higher than that in TheraP (38%).⁷

The combination of ¹⁷⁷Lu-PSMA-617 plus pembrolizumab is being evaluated in the phase I PRINCE trial (NCT03658447). It has been hypothesized that by potentially inducing immunogenic cell death, ¹⁷⁷Lu-PSMA-617 may act synergistically with pembrolizumab to enhance the depth and durability of response. In this trial, mCRPC patients with high PSMA expression (SUVmax ≥ 20 in an index lesion, SUVmax > 10 for all lesions ≥ 10mm), and no FDG positive/PSMA negative lesions on paired baseline PET/CT screening, received up to 6 cycles of ¹⁷⁷Lu-PSMA-617 (starting at 8.5 GBq, reducing by 0.5 GBq with each cycle) every 6 weeks in conjunction with 200 mg of pembrolizumab every 3 weeks for up to two years. The study schema is as follows: 

There were 37 patients (73% had received prior docetaxel, and 100% had received a prior ARPI) that received a median of 5 cycles (range 2 to 6) of ¹⁷⁷Lu-PSMA-617 and 12 doses (range 6 to 19) of pembrolizumab. The median follow up was 16 months, over which time the 50% PSA response rate was 76% and 7/10 (70%) patients with RECIST-measurable disease had a partial response. The median rPFS was 11.2 months. The median PSA-progression-free survival was 8.2 months, and the median overall survival was 17.8 months.

Common (≥10%) treatment-related adverse events were mainly grade 1-2, including xerostomia (78%), fatigue (43%), pruritus (27%), nausea (27%), and rash (24%). Hematologic treatment-related adverse events included grade 2-3 anemia (8%), grade 1-2 thrombocytopenia (16%), and grade 1 neutropenia (3%). Grade 3 immune-related adverse events occurred in 10 (27%) patients with no dominant manifestation. There were 5 (14%) patients who discontinued pembrolizumab due to toxicity.

Another ¹⁷⁷Lu-PSMA-617 + immunotherapy combination currently under investigation in the mCRPC setting is the combination of ¹⁷⁷Lu-PSMA-617 plus ipilimumab/nivolumab, which is being evaluated in the phase II EVOLUTION trial.

In the neoadjuvant setting, ¹⁷⁷Lu-PSMA-617 +/- ipilimumab is being evaluated in the NEPI trial of very high-risk prostate cancer patients who are planned for a radical prostatectomy.

Dr. Emmett concluded by noting the following regarding radioligand combination therapy approaches:

• Moving radioligand treatment into an earlier (pre-chemotherapy) setting is important, as it is better tolerated than chemotherapy regimens and may potentially improve overall survival outcomes.
• Need to ensure an additive benefit when combining radioligand therapy with other agents.
• We need to define the natural place of radioligand therapy +/- combinations in the prostate cancer journey:
  • Primary role or as an adjuvant treatment

Presented by: Louise Emmett, BSc(HONS), MBChB, FRACP, FAANMS, MD, The University of New South Wales (UNSW), Sydney, Australia

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024. 

References:

1. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385:1901-1103.
2. Hofman MS, Emmett L, Sandhu S, et al. [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
3. Swiha M, Papa N, Sabahi Z, et al. Development of a Visually Calculated SUVmean (HIT Score) on Screening PSMA PET/CT to Predict Treatment Response to 177Lu-PSMA Therapy: Comparison with Quantitative SUVmean and Patient Outcomes. J Nucl Med. 2024.
4. Emmett L, Subramaniam S, Crumbaker M, et al. [177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024:S1470-2045(24)00135-9
5. Kostos LK, Buteau JP, Kong G, et al. LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [177Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(Suppl 6):TPS278.
6. Sheehan B, Neeb A, Buroni L, et al. Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer. Clin Cancer Res. 2022;28(14): 3104-15.
7. Sandhu S, Joshua AM, Emmett L, et al. LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41: Suppl 16. 

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer imaging session. Dr. John Nikitas presented an update from the PSMA-dRT trial, a randomized phase III trial of PSMA-PET/CT prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer imaging session. Dr. Isabel Rauscher presented the results of an analysis of ¹⁸F-rhPSMA-7 and ¹⁸F-flotufolastat PET-guided salvage radiotherapy in recurrent prostate cancer.

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8^th and June 11^th, 2024 was host to a prostate cancer imaging session. Dr. Atefeh Zamanian provided insights from the 3TMPO study evaluating the tumor sink effect on PSMA-PET/CT in metastatic prostate cancer and its implications for PSMA radioligand therapy.

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between May 31 and June 4 was host to the Session: Managing Variant Histologies in Urothelial and Renal Cell Cancers. Dr. Sumanta Kumar Pal discussed What Is Variant Histology Renal Cell Cancer and What Are the Available Treatment Options to date.

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between May 31 and June 4 was host to the Session: Managing Variant Histologies in Urothelial and Renal Cell Cancers. Dr. Jean Hoffman-Censits delve into what is considered variant Histology urothelial cancer and what are the available treatment options in 2024.

The landscape of first-line management for urothelial cancer has radically changed over the past year and continues to evolve. With the approval of new agents like enfortumab vedotin (EV) combined with pembrolizumab, as well as new regimens such as nivolumab and gemcitabine cisplatin (GC), there are now a variety of options for treating patients with urothelial cancer (UC).(1,2) However, the majority of trials leading to these changes and updates in clinical practice have predominantly included patients with pure UC. A major limitation of these trials is that they often lump variant histology (VH) into a single category rather than splitting outcomes data into different variants. This approach assumes that "variant histology" is a single entity, ignoring the fact that many variants exist, each with distinct prognoses, outcomes, and responses to platinum-based chemotherapy or immunotherapy.

The most common VH is squamous cell carcinoma, which was found to represent 31% of VH in a recent report on the distribution of histologic subtypes of bladder cancer. This was followed by neuroendocrine (17%), adenocarcinoma and sarcomatoid variants (16%), with the least common being plasmacytoid.(3)

After the presentation of the EV-302 study at ESMO 2023, the frontline therapy for locally advanced unresectable or advanced UC has shifted to EV + pembrolizumab. Ideally, patients who progress after this first line should transition to GC. (2) Another frontline treatment option is nivolumab + GC, as reported in the CheckMate 901 trial. (1) Additional options for patients after progression include erdafitinib, sacituzumab govitecan, and trastuzumab deruxtecan. However, given the numerous available options and tools for improving patient selection, it remains challenging to determine the optimal choice for the first-line setting and after progression.

There are many different variants considered VH for UC. Dr. Hoffman-Censits delved into each one of them separately, which we will discuss below.

Small cell cancer is typically an aggressive tumor, but it often responds well to chemotherapy. Brain involvement is frequently seen at presentation, and recurrence rates are high. The treatment for this histologic variant has been extrapolated from data on small cell lung cancer (SCLC). Etoposide (EP) neoadjuvant chemotherapy (NAC) has been recommended, even for tumors staged as cT1. It has been shown that NAC followed by local treatment improves survival outcomes compared to radical cystectomy (RC) alone. However, any residual small cell cancer at the RC pathology is associated with worse outcomes than residual UC alone. (4)

Data supporting immune checkpoint inhibitors for small cell cancer has been published. However, the preferred approach remains NAC followed by surgery and possibly adjuvant nivolumab. With our current treatment paradigm of using upfront EV + Pembrolizumab for the frontline setting of UC, this approach could be considered and discussed for patients with small cell cancer according to Dr. Hoffman-Censits.

Three clinical trials examining treatment options for the small cell variant are ongoing:

• In the neoadjuvant setting, a trial exploring Atezolizumab with Platinum and Etoposide Chemotherapy Followed by Cystectomy for Patients with Localized Small Cell Neuroendocrine Bladder Cancer (NCT05312671).
• In the first-line setting of advanced extrapulmonary neuroendocrine tumors, a phase II/III trial (NCT05058651) compares the effect of atezolizumab in combination with standard chemotherapy with a platinum drug (cisplatin or carboplatin) and etoposide versus standard therapy alone.
• In the second-line setting, the LASER trial (NCT06228066) is evaluating Lurbinectedin with or without Avelumab in small cell carcinoma of the bladder.

Sarcomatoid differentiated variant histology of urothelial carcinoma (UC) is characterized by malignant spindle cells with a nonspecific morphologic appearance. Retrospective studies generally do not show a significant benefit from NAC or adjuvant chemotherapy (AC), but the receptivity in these studies is low. (5) However, a pooled analysis indicates that NAC can improve overall survival (OS). (6) One specific NAC regimen—cisplatin (35 mg/m²), gemcitabine (800 mg/m²), and docetaxel (35 mg/m²) on days 1 and 8, with G-CSF support every 21 days for four cycles—followed by radical cystectomy (RC) has shown promising results, with a ypCR rate of 38% and a <ypT2 rate of 50%. Additionally, sarcomatoid UC often exhibits high PD-L1 expression, with an overall response rate (ORR) of 35-50% to immune checkpoint inhibitors (ICI) in the first-line setting.

Squamous cell carcinoma (SCC) of the urothelial tract is an aggressive variant that can present as locally advanced disease often. One of the notable clinical features is hypercalcemia, which requires careful monitoring of the metabolic panel. Histologically, SCC exhibits keratinization and intercellular bridges, making it indistinguishable from squamous carcinoma of other primary sites.

In a prospective study involving ifosfamide, paclitaxel, and cisplatin, the overall response rate (ORR) was 25% in eight patients with SCC. Data from the SEER database (n=1371) indicates a survival benefit with adjuvant chemotherapy. (7)

SCC shows poorer progression-free survival (PFS) and overall survival (OS) compared to conventional urothelial carcinoma (UC). Specifically, PFS for SCC treated with cisplatin and paclitaxel (CP) was 1.9 months versus 4.8 months for UC (P < .01), and median OS was 9.2 months for SCC compared to 20.7 months for UC (P < .01). Additionally, SCC has a lower ORR to enfortumab vedotin (EV) or EV plus pembrolizumab (EV+P), at 17% versus 70% for UC (P < .01), with a median PFS of 3.4 months for SCC compared to 15.8 months for UC (P < .01). (3)

The micropapillary variant of urothelial carcinoma is characterized by HER2 activating alterations. This molecular feature makes it a potential candidate for targeted therapies. In the DESTINY-PanTumor02 Phase II trial, trastuzumab deruxtecan was evaluated in 41 patients with previously treated bladder cancer, including those with micropapillary histology. The overall response rate (ORR) was 56.3% in tumors with IHC3+ HER2 expression and 35% in tumors with IHC2+ expression. These findings highlight the efficacy of HER2-targeted therapy in this aggressive variant and support its use in clinical practice for patients with HER2-positive micropapillary urothelial carcinoma. (8)

Urachal cancer is a rare malignancy accounting for <1% of bladder cancers. This is an aggressive disease with the overall survival for recurrent or metastatic disease currently less than two years. Highlighted at ASCO 2024 was a prospective study (ULTMA; KCSG GU20-03) assessing modified FOLFIRINOX in 21 patients treated between 2021 and 2023. The ORR was 61.9%, with complete responses (CR) in 2 patients (9.5%), partial responses (PR) in 11 patients (52.4%), and stable disease (SD) in 8 patients (38.1%). Progression-free survival (PFS) was 9.3 months, and overall survival (OS) was 19.7 months. (9) Additionally, the MD Anderson Cancer Center (MDACC) retrospective experience presented at ASCO GU 2024 reviewed outcomes with the GemFLP regimen (Gemcitabine, 5-FU, and cisplatin) in 40 patients with urachal cancer, further supporting the efficacy of tailored chemotherapy approaches for this rare and aggressive variant. (10)

Dr. Hoffman-Censits discussed the application of EV for variant histology urothelial carcinoma , noting that while the population of patients with variant histology was reported in published trials, the response of variant histology to EV was not consistently reported. She highlighted two ongoing studies with immune checkpoint inhibitors (IO) in this context: "Enfortumab vedotin plus pembrolizumab in the treatment of locally advanced or metastatic bladder cancer of variant histology: A phase II study (NCT05756569)" and "A phase II multicenter study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors (E-VIRTUE) (NCT06041503) that hopefully would give us some answers into this the treatment of this rare variants.

The UNITE study, a large retrospective cohort, assessing the efficacy of EV in advanced UC including variant histology, included a total of 260 patients treated with EV monotherapy. (n=70), 66 patients with UC and variant histology, and 4 with pure variant histology. The ORR in variant histology was 42% compared to 58% in patients with pure UC (n=142), this was not significant (p=0.056). A detailed response according to different variant histology groups is shown in the table below. (11)

Furthermore, the median OS in pure UC was 14.8 months, compared to 13.4 months (p=0.064) in patients treated with EV monotherapy.

Dr. Hoffman-Censits presented updated outcomes from the UNITE study, now encompassing a total of 566 patients, including 200 with variant histology. Among these, UC predominant tumors (n=151), those with ≥50% variant histology (n=35), and pure variant histology cases (n=14) were analyzed. The study revealed a 0% ORR in pure variant histology, regardless of subtype (0/5 SCC, 0/3 PC, 0/1 Sarc, 0/2 Small Cell), as well as no response observed with any small cell component, irrespective of percentage.

In the UNITE study, outcomes were evaluated for 116 patients treated with Sacituzumab Govitecan, with 44 of them having variant histology. The overall response rate (ORR) for all patients was 24%, comparable to 23% for those with any variant histology. When analyzed based on specific VH groups, the results are detailed in the table below.

SMART is an open-label, non-randomized Phase 2 trial designed to evaluate treatment outcomes in patients with locally advanced (unresectable) or metastatic genitourinary (GU) tumors of specific histologies, including small cell carcinoma, squamous cell carcinoma, primary adenocarcinoma of the bladder or urinary tract, renal medullary carcinoma (RMC), or squamous cell carcinoma of the penis. Patients will receive Sacituzumab Govitecan (SG) or SG and concomitant atezolizumab, results are awaited. (11)

Of note, the CheckMate 901 study included a significant proportion of patients with variant histology, comprising 51% in the Nivolumab + GC arm and 53% in the GC arm. However, the outcomes for this specific population have not yet been reported. (1)

With our new treatment paradigms, patients with variant histology in 2024 should be approached carefully. Dr. Hoffman-Censits suggests initiating treatment with platinum-based chemotherapy. For those with biomarker-positive tumors, she advocates for prioritizing other drugs as the initial treatment option.

These are the key takeaways Dr. Hoffman-Censits used to conclude her presentation:

• Prospective trials face challenges in funding and accrual, requiring larger sample sizes for meaningful results.
• Basket studies offer opportunities but have limited capacity for extensive clinical development.
• Reporting practices of variant histology in large prospective studies vary, potentially impacting data interpretation.
• Historical practices of excluding subtypes/women/African American may have contributed to the perception of bladder cancer as predominantly affecting white males, highlighting the need for more inclusive trial design.
• There are now two potent frontline regimens available for bladder cancer, raising questions about how to maximize their combined benefits.
• Biomarker-selected and unselected agents approved for second-line use in urothelial carcinoma (UC) provide an expanding toolkit for treating non-UC subtypes.
• Biopsying at disease progression is recommended to inform treatment sequencing and target specific subtypes, particularly in variant histologies.
• The "rainbow" of available treatments presents challenges for FDA approval in data-scarce areas like micropapillary and small cell carcinoma.

Presented By: Jean H. Hoffman-Censits, MD, Genitourinary medical oncologist at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and The Greenberg Bladder Cancer Institute at Johns Hopkins.

Written By: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between May 31^st and June 4^th.

References:

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7. Abdel-Rahman O. Squamous Cell Carcinoma of the Bladder: A SEER Database Analysis. Clin Genitourin Cancer. 2017 Jun;15(3):e463-e468. doi: 10.1016/j.clgc.2016.10.007. Epub 2016 Oct 28. PMID: 27876505.
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