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EAU Annual Congress 2022

EAU 2022: PSMA Theranostics and Novel Approaches to Treatment in mCRPC

(UroToday.com) The 37th Annual European Association of Urology Congress held in Amsterdam, Netherlands between July 1st, and 4th 2022 was host to a session about innovative future treatment options for metastatic castration-resistant prostate cancer (mCRPC). Dr. Alicia Morgans was tasked with discussing prostate-specific membrane antigen (PSMA) theranostics and novel approaches to treatment of metastatic castration-resistance prostate cancer (mCRPC).

 

Dr. Morgans began her presentation by giving an overview of the current mCRPC therapeutic landscape:

 

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She notes that as these agents demonstrate efficacy in the later stages of mCRPC, these agents will continue to be moved further up in the treatment paradigm for such patients.

 

When considering treatment options for patients in this disease space, one must consider these clinical factors/general principles:

  1. Prior treatments  Agents with a novel mechanism of action are preferred
  2. Which options are available at my practice location?
  3. Are metastases visceral or bone only?
  4. Is the patient a candidate for chemotherapy?
  5. Is there small cell/neuroendocrine differentiation?
  6. Are there targetable DNA-repair gene defect (DRD) mutations or is the tumor microsatellite instability (MSI) high?
  7. What are the clinical trial options available?

 

As we continue to evolve the field of precision medicine and offer patients appropriate targeted therapy, Dr. Morgans emphasized that DNA repair gene alterations are common in metastatic prostate cancer:1,2

  1. Of men with metastatic prostate cancer, 11.8% have a germline alteration in 16 DDR genes
    1. Age and family history do not affect mutation frequency
  2. Of men with mCRPC, 23% harbor DNA repair alteration
    1. The frequency of DNA repair alterations increases with disease progression

 

 

 

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The importance of testing for both somatic and germline mutations cannot be overstated. As we consider treatment with 2 poly (ADP-ribose) polymerase (PARP) inhibitors, the frequency of DDR mutations such as BRCA2 (10-11%) becomes especially important.

 

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These findings have been reflected in the latest EAU guidelines for mCRPC patients, which state that physicians should consider germline testing in men with metastatic prostate cancer (weak rating).

 

Dr. Morgans next presented results of PROfound. PROfound was a randomized, open-label, phase III trial evaluating the efficacy and safety of olaparib vs enzalutamide or abiraterone in patients with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in homologous recombination repair whose disease had progressed on prior new hormonal agent therapy.

 

For PROfound, qualifying tumour tissue homologous recombination repair alterations were centrally and prospectively identified using an investigational next-generation sequencing test. This study included two cohorts:

  • Cohort A included patients with alterations in BRCA1, BRCA2 or ATM
  • Cohort B patients included any one of 12 other homologous recombination repair alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L)

 

Patients were randomized 2:1 to olaparib (300 mg bid) or the physician’s choice of enzalutamide (160 mg/day) or abiraterone (1000 mg/day + prednisone 5 mg BID). The primary endpoint was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review and analyzed via a stratified log-rank test. Crossover to olaparib was allowed after blinded independent central review progression.

 

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In the overall cohort, Olaparib was shown to improve median PFS from 3.5 months in the control arm to 5.8 months with Olaparib (HR: 0.49, 95% CI: 0.38 – 0.63, p<0.001).

 

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With regards to OS, Olaparib improved OS in Cohort A (19.1 months versus 14.7 months, HR: 0.69, 95% CI: 0.50 – 0.97, p=0.02) and the overall cohort (17.3 months versus 14.0 months, HR: 0.79, 95% CI: 0.61 – 1.03).3

 

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Next, Dr. Morgans presented a summary of the VISION trial. VISION is a phase III study of 177Lu-PSMA-617 in patients with mCRPC with the following criteria:

  • 68Ga-PSMA-11 PET/CT positive scan
  • Received at least one ARI (enzalutamide or abiraterone)
  • Treated with at least 1 but no more than 2 previous taxanes
  • ECOG PS 0-2

 

Patients were randomized in a 2:1 fashion to either 177Lu-PSMA-617 7.4 GBq q6 weeks x 6 + best supportive/standard of care or best supportive/standard of care alone. The alternate primary endpoints were OS and rPFS.

 

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With regards to OS, 177Lu-PSMA-617 use was associated with a 38% risk reduction for death (median OS 15.3 versus 11.3 months, HR: 0.62, 95% CI: 0.52- 0.74), p<0.001).

 

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Consistent results were seen for rPFS, with 177Lu-PSMA-617 use reducing rPFS hazard by 60% (median rPFS 8.7 versus 3.4 months, HR: 0.40, 99.2% CI: 0.29 – 0.57, p<0.001).

 

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While a higher rate of high-grade (grade 3-5) treatment-emergent adverse events was observed with 177Lu-PSMA-617 (28.4% vs 3.9%), overall therapy was well tolerated. However, it bears note that there were 5 deaths attributable to 177Lu-PSMA-617 treatment. In terms of specific adverse events, treatment with 177Lu-PSMA-617 + SOC was associated with increased rates of bone marrow suppression, xerostomia, and nausea and vomiting.4

 

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Dr. Morgans next moved on to the TheraP trial which included patients with mCRPC post-docetaxel, rising PSA and PSA≥20 ng/ml. Notably, patients in this trial had to have both a 68Ga-PSMA-11 and FDG PET/CT study to be potentially eligible for this study.

  1. Positive 68Ga-PSMA-11 study (SUV max >20 at any site)
  2. No FDG positive/PSMA negative sites of disease

 

Patients were randomized in a 1:1 fashion to 177Lu-PSMA-617 (8.5 GBq IV q6 weekly up to 6 cycles) or cabazitaxel (20mg/m2 IV q3 weekly, up to 10 cycles).

 

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Compared to cabazitaxel, 177Lu-PSMA-617 was shown to improve PFS (HR: 0.62, 95% CI: 0.45 – 0.85, p=0.0028), however this treatment effect was not constant with respect to time, as reflected by the restricted mean survival time (see below). Looking at this in a more granular fashion, consistent improvements were seen for both rPFS (HR: 0.65) and PSA-PFS (HR: 0.60).

 

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As was presented recently at ASCO 2022, PSMA-PET/CT can act as a predictive biomarker. Although patients treated with 177Lu-PSMA-617 benefit irrespective of SUV levels, patients with mean SUV >=10 experience a significantly better PSA response (PSA50-RR) as demonstrated by the waterfall plot below.

 

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When evaluating the PSA50-RR of 77Lu-PSMA-617 versus cabazitaxel, a PSMA SUVmean >=10 had an OR of 12.2 (95% CI: 3.4 – 59), compared to an OR of 2.2 for patients with PSMA SUVmean <10.

 

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For the final portion of her presentation, Dr. Morgans presented recent updates and novel trials underway in prostate cancer.

 

PROpel is a global, randomized, double-blind phase III trial in men with mCRPC. Eligible participants had received no prior abiraterone and had stopped an alternative ARI more than 12 months prior to enrollment. Docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) was allowed. Patients were stratified by site of distant metastasis and whether they had received docetaxel for mHSPC. Patients were then randomized to receive full-dose abiraterone 1000 mg daily with either placebo or full-dose olaparib 300 mg BID. The primary endpoint was investigator-assessed rPFS. OS was the key secondary endpoint.

 

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PROpel met its primary endpoint with the addition of olaparib to abiraterone resulting in a 34% reduction in progression (rPFS HR = 0.66, 95% CI 0.54-0.81; P < 0.0001). The addition of olaparib improved median rPFS by 8.2 months (24.8 versus 16.6). This finding was confirmed on blinded independent central review, on which olaparib resulted in a 39% improvement in rPFS and 11.2 month improvement in rPFS. 

 

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Significantly, Olaparib showed consistent rPFS benefits in both the HRR mutated (HR: 0.50, 95% CI: 0.34- 0.73) and non-HRR mutated subgroups (HR: 0.76, 95% CI: 0.60 – 0.97). OS data, to date, remain immature.

 

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MAGNITUDE is a randomized, double-blind phase 3 study. In eligible mCRPC patients, ≤4 months of prior abiraterone acetate/prednisone for mCRPC was allowed. Patients with (HRR biomarker positive: ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR biomarker negative) were randomized 1:1 to receive niraparib 200 mg once daily + abiraterone acetate/prednisone or placebo + abiraterone acetate/prednisone. The primary endpoint was rPFS. assessed by blinded independent central review in the BRCA1/2 group followed by all HRR biomarker positive patients. Secondary endpoints were time to initiation of cytotoxic chemotherapy, time to symptomatic progression, and overall survival. Other endpoints included time to PSA progression and objective response rate. The trial design for MAGNITUDE is as follows:

 

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Addition of Niraparib to abiraterone was associated with rPFS improvements in both the HRR BM+ cohort (16.5 versus 13.7 months, HR: 0.73, 95% CI: 0.56 – 0.96) and BRCA 1/2-mutated patients (16.6 versus 10.9 months, HR: 0.53, 95% CI: 0.36 – 0.79).

 

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Dr. Morgans concluded her talk with the following take home messages:

  1. Treatment of men with mCRPC continues to evolve rapidly
  2. General principles continue to hold true
    1. Use of a second AR targeted agent after the first has failed is generally not effective
    2. Germline and somatic genetic testing are standard of care in mCRPC
  3. 177LU-PSMA-617 is an option after progression of disease on docetaxel and an AR targeted agent
  4. Combinations of PARP inhibitors with ARIs and numerous other approaches are on the horizon for future treatment of mCRPC

 

Presented by: Alicia K. Morgans, MD, MPH, Associate Professor, Department of Medicine, Medical Director of the Survivorship Program at Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, MA

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2022 European Association of Urology (EAU) Annual Hybrid Meeting, Amsterdam, NL, Fri, July 1 – Mon, July 4, 2022. 

References:

  1. Robinson D, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-28.
  2. Pritchard X, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016;375(5):443-53.
  3. Hussain M, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;383:2345-57.
  4. Sartor AO, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021