PSMA and Beyond 2025: Keynote Lecture: Improving Outcomes with Combination Therapy

(UroToday.com) The 2025 PSMA and Beyond annual meeting featured a Keynote Lecture by Dr. Michael Hofman discussing improving outcomes with combination therapy. Dr. Hofman started his lecture by highlighting the 5 randomized trials of ¹⁷⁷Lu-PSMA-617 that have been published, including TheraP,^1,2 VISION,³ ENZA-p,⁴ PSMAfore,⁵ and UpFrontPSMA:⁶

There are certain mechanisms of resistance in patients with mCRPC, which include:

Underlying PSMA-negative disease
The role of the tumor microenvironment
Micrometastatic disease not receiving adequate radiation from ¹⁷⁷Lu
Underlying molecular factors which confer radio-resistance

In practice, we see all types of patient responses to ¹⁷⁷Lu-PSMA-617, including complete response after 4 cycles, and progressive responses after a full 6 cycles:

But we may also see stable disease by early progression, or primary progression:

There are several ways to potentially overcome resistance, including the utilization of radiosensitizers:

The first trial Dr. Hofman discussed regarding ¹⁷⁷Lu-PSMA-617 in combination with other agents was the ENZA-p trial⁴ assessing ¹⁷⁷Lu-PSMA-617 + enzalutamide versus enzalutamide monotherapy. The impetus for this study is that enzalutamide has been shown to upregulate expression of PSMA on subsequent imaging. ENZA-p included mCRPC patients not previously treated with chemotherapy or androgen receptor pathway inhibitors (prior abiraterone and/or docetaxel for hormone-sensitive disease were allowed), ⁶⁸Ga-PSMA-positive disease on PET, and at least 2 risk factors associated with early progression on enzalutamide. In the enzalutamide + ¹⁷⁷Lu-PSMA-617 arm, 81% of patients received four doses of ¹⁷⁷Lu-PSMA-617. PSA50 and PSA90 improved with ¹⁷⁷Lu-PSMA-617 + enzalutamide. Over a median follow up of 20 months (IQR 18-21), PSA progression free survival was longer with enzalutamide + ¹⁷⁷Lu-PSMA-617 vs enzalutamide-alone (median 13 vs 7.8 months; HR 0.43, 95% CI 0.29-0.63, p < 0.001). There was also a trend towards improved radiographic progression free survival favoring ¹⁷⁷Lu-PSMA-617 (HR 0.68, 95% CI 0.45-1.03):

A total of 96 deaths were reported after a median follow-up of 34 months (IQR 29-39): 53 among those assigned enzalutamide-alone and 43 among those assigned enzalutamide + ¹⁷⁷Lu-PSMA-617. Overall survival was longer in the enzalutamide + ¹⁷⁷Lu-PSMA-617 group than the enzalutamide-alone group: median 34 months versus 26 months (HR 0.55, 95% CI 0.36 to 0.84; p = 0.005):⁷

Health-related quality of life was rated by 154 of 162 participants (95%). With regards to deterioration-free survival, this favored enzalutamide + ¹⁷⁷Lu-PSMA-617 for both physical function (HR 0.51, 95% CI 0.36 – 0.72) and overall health status (HR 0.47, 95% CI 0.33 – 0.67):

In additional work from the ENZA-p trial presented at EANM 2024, Dr. Hofman notes that in the enzalutamide arm, a decrease in SUVmean at day 15 was associated with a median PSA progression free survival of 12.5 months, compared to 5.8 months for an increase in SUVmean (p = 0.016). In the enzalutamide + ¹⁷⁷Lu-PSMA-617, there was no difference in median PSA progression free survival (p = 0.90):

Thus, the shorter progression free survival with increased PSMA SUVmean on enzalutamide monotherapy is mitigated with the addition of ¹⁷⁷Lu-PSMA-617.

Dr. Hofman then discussed PARP inhibitors as a radiosensitizer for ¹⁷⁷Lu-PSMA-617, with the following schematic:

The combination trial for ¹⁷⁷Lu-PSMA-617 + PARP inhibitors is the LuPARP trial, which is a phase I trial of ¹⁷⁷Lu-PSMA-617 and olaparib with the following trial schema:

For treatment-related adverse events, no dose limiting toxicities were reported across the dose levels, and there were no grade 4 adverse events. One treatment-related serious adverse event occurred (febrile neutropenia), and dose delay due to hematological toxicity occurred in 3 (9%) patients (cohorts 2, 5, and 6). Dose reduction was required in 4 patients (12%), with 3 due to hematological toxicity and 1 due to xerostomia. The recommended phase 2 dose was 7.4 Gb of ¹⁷⁷Lu-PSMA-617 in conjunction with olaparib 300 mg twice daily on days -4 to 18 of each 6 weekly cycle. In the overall cohort (i.e., Cohorts 1 to 9), the PSA50 and PSA90 response rates were 65% and 47%, respectively, and the objective response rate by RECIST v1.1 criteria was 78%:

Next, Dr. Hofman discussed the LuCAB trial, which was designed to assess whether cabazitaxel combined with ¹⁷⁷Lu-PSMA-617 could improve response rates and durability of treatment in patients with mCRPC. The LuCAB phase I/II trial is a single center, ongoing trial combining ¹⁷⁷Lu-PSMA-617 up to six cycles with cabazitaxel up to 12 doses, with cabazitaxel dose escalation:

The primary objective was assessing the maximal tolerated dose of cabazitaxel and ¹⁷⁷Lu-PSMA-617, with secondary objectives including adverse events, PSA50, response rate, radiographic progression free survival, PSA progression free survival, overall survival, objective response rate, and evaluation of pain and health-related quality of life.

The phase I/II ongoing ALPHABET trial is testing the combination of ¹⁷⁷Lu-PSMA-I&T + radium-223. The hypothesis is: can radium-223 in combination with ¹⁷⁷Lu-PSMA-I&T lead to deeper and more durable response? Patients will receive ¹⁷⁷Lu-PSMA-I&T 7.4 GBq IV every 6 weeks + radium-223 IV every 6 weeks for up to 6 cycles/doses, with the following clinical trial design:

The co-primary objective is determining the maximum tolerated dose of radium-223 when combined with ¹⁷⁷Lu-PSMA-I&T, and the PSA50 rate. Secondary objectives include adverse events, efficacy through radiographic and PSA progression free survival, overall survival and objective response rate, as well as evaluation of pain and health related quality of life.

Next, Dr. Hofman discussed the PRINCE trial, which is a phase 1 trial of ¹⁷⁷Lu-PSMA-617 in combination with pembrolizumab in mCRPC, first presented at ESMO 2021. The trial design for PRINCE is as follows:

Among 37 patients, they received a median of 4 cycles of ¹⁷⁷Lu-PSMA-617 and 8 doses of pembrolizumab. Treatment-related adverse events (>=10%) were low grade (1-2) and included xerostomia (76%), fatigue (43%), nausea (24%), rash (22%), pruritus (19%), elevated ALT (11%), diarrhea (11%), and bone pain (11%). The objective response rate according to RECIST v1.1 was 78%, with a PSA50 response of 73%:

The 24 week radiographic progression free survival rate was 65% (95% CI 45-79), and the 24 week PSA progression free survival rate was 68% (95% CI 58-81):

The hypothesis of the EVOLUTION trial is that the combination of a radionuclide (¹⁷⁷Lu-PSMA-617) and immune checkpoint inhibitors (ipilimumab and nivolumab) may act synergistically, whereby ¹⁷⁷Lu-PSMA-617 may induce immunogenic cell death enhancing the clinical efficacy of ipilimumab/nivolumab, leading to improved long-term clinical outcomes. EVOLUTION will randomize 100 patients in a 2:1 fashion to either the intervention arm of ¹⁷⁷Lu-PSMA-617 7.5 GBq every 6 weeks for up to 6 doses plus ipilimumab 3 mg/kg every 6 weeks x 4 doses and nivolumab 1 mg/kg every 3 weeks x 8 doses during induction, followed by nivolumab 480 mg every 4 weeks x 18 doses during maintenance or ¹⁷⁷Lu-PSMA-617 alone. The primary endpoint is 12-month PSA progression-free survival. The trial schema is as follows:

Results from ENVISION will be presented at the upcoming 2025 ASCO annual meeting.

Moving to the mHSPC disease space, Dr. Hofman discussed the UpFrontPSMA trial,⁶ which included patients with de novo high-volume mHSPC who had received ≤4 weeks of ADT and had a PSA >10 ng/ml at diagnosis. Eligibility was limited to those patients with evidence of high tumor uptake and high-volume disease on PET scans. Patients were also required to have the majority of their metastatic disease demonstrating PSMA positivity. Eligible patients were randomized to:

Experimental arm: ¹⁷⁷Lu-PSMA-617 7.5 GBq x 2 cycles + docetaxel 75 mg/m² x 6 cycles
Control arm: Docetaxel 75 mg/m² x 6 cycles

Between May 2020 and April 2023, 130 patients were recruited and underwent randomization (experimental: 63, control: 67). The median follow-up was 2.5 years. For the primary outcome, an undetectable PSA at week 48 was observed in 41% of patients in the ¹⁷⁷Lu-PSMA + docetaxel arm versus 16% of patients in the docetaxel control arm (OR 3.88, 95% CI 1.61–9.38, p = 0.002). An undetectable PSA at any point was observed in 51% and 32% of patients, respectively (OR 2.14, p = 0.042). There were no differences in undetectable PSA levels at week 12 between the two arms (p = 0.9).

Time-to-event analyses demonstrated that patients in the experimental arm had superior PSA progression-free survival (median: 31 versus 20 months; HR 0.60, p = 0.039) and freedom from castration resistance (HR 0.60, p = 0.033). Radiographic progression-free survival similarly favored ¹⁷⁷Lu-PSMA + docetaxel (HR 0.58, p = 0.067). Adverse events were similar in both arms, with grade 3–4 events in 27–29% of cases, and there were no new safety signals. As expected, patients in the ¹⁷⁷Lu-PSMA arm had a higher frequency of dry mouth (37% versus 0% – all grade 1–2).

The POPSTAR2 phase 2 trial is assessing whether stereotactic body radiotherapy is effective at controlling visible disease and whether adding ¹⁷⁷Lu-PSMA-617 maximizes control of both visible and invisible disease. There will be 96 men recruited with oligometastatic prostate cancer and 1 to 5 sites of non-visceral metastatic disease on PSMA PET CT. There has to be 1+ extra pelvic site of disease, no recent or concurrent ADT, and PSMA SUVmax greater than the liver. The trial schema is as follows:

The final combination trial discussed by Dr. Hofman was the LuTectomy trial,⁸ with initial results published in 2023. This is a single-center, single-arm, phase 1/2 study assessing the administration of ¹⁷⁷Lu-PSMA-617 prior to radical prostatectomy in men with high-risk localized prostate cancer:

This study included 20 patients, 10 in Cohort A (received one cycle of therapy) and 10 in Cohort B (received two cycles of therapy) followed by radical prostatectomy six weeks later. Overall, nine (45%) patients achieved >50% PSA decline, histopathological evidence of treatment effect was seen in 16 (80%) patients, one had minimal residual disease on final histology, and no patients achieved a complete pathological response. A summary of results from LuTectomy is as follows:

Dr. Hofman concluded his keynote lecture by discussing improving outcomes with combination therapy with the following take home points:

Combination trials are needed for theranostics v2
There are many trials underway
Combinations may include drugs, external beam radiotherapy or surgery
There are also combination isotopes
There is a move towards earlier use

Presented by: Michael Hofman, MBBS, Peter MacCallum Cancer Centre, 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 2025 PSMA and Beyond Annual Meeting, Los Angeles, CA, Fri, Mar 28 – Sat, Mar 29, 2025.

References:

Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804.
Hofman MS, Emmett L, Sandhu S, et al. Overall survival with [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): Secondary outcomes of a randomized, open-label, phase 2 trial. Lancet Oncol. 2024 Jan;25(1):99-107.
Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
Emmett L, Subramaniam S, Crumbaker M, et a. [¹⁷⁷Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): An open-label, multicentre, randomized, phase 2 trial. Lancet Oncol. 2024 May;25(5):563-571.
Morris MJ, Castellano D, Herrmann K, et al. ¹⁷⁷Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naïve patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): A phase 3, randomized, controlled trial. Lancet 2024 Sep 28;404(10459):1227-1239.
Azad AA, Bressel M, Tan H, et al. Sequential [(177)Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone sensitive prostate cancer (UpFrontPSMA): A multicentre, open label, randomized, phase 2 study. Lancet Oncol. 2024 Oct;25(10):1267-1276.
Emmett L, Subramaniam S, Crumbaker M, et al. Overall survival and quality of life with [¹⁷⁷Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): Secondary outcomes from a multicentre, open-label, randomized, phase 2 trial. Lancet Oncol. 2025 Feb 12 [online ahead of print].
Eapen RS, Buteau JP, Jackson P, et al. Administering [¹⁷⁷Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localized Prostate Cancer (LuTectomy): A Single-centre, single-arm, phase 1/2 study. Eur Urol. 2023 Oct 25:S0302-2838(23)03087-7.

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