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ESMO East 2023: Updates in Prostate Cancer with Dr Bruno Bastos

Updated: Jan 30

Presentation by Bruno Bastos, MD, Miami Cancer Center



At the 2023 ESMO East review conference presented by Total Health in Fort Lauderdale, Florida, Dr Bruno Bastos from Miami Cancer Institute presented updates in prostate cancer from this year’s European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain.  The abstracts selected featured new developments for targeted therapies in prostate cancer, including Lutetium (177Lu-PSMA-617), a type of targeted radiotherapy treatment for metastatic, castration-resistant prostate cancer (mCRPC) with expression of prostate-specific membrane antigen (PSMA), and niraparib, a poly-ADP ribose polymerase (PARP) inhibitor type drug for patients with BRCA mutation positive (BRCA+) mCRPC.

 

ENZA-P (ANZUP 1901)

The first abstract detailed results from the ENZA-p Trial (NCT04419402), a randomized phase II trial comparing the use of first line (1L) enzalutamide, an antiandrogen drug, and the current standard of care, in combination with 177Lu-PSMA-617, versus enzalutamide alone, in patients with mCRPC having poor risk features (BOX 1). The rationale for a trial combining these two agents was based on previous findings that a certain proportion of mCRPC patients are ‘early progressors’ (within 3 months) when treated with enzalutamide alone.  In addition, the use of enzalutamide causes an initial upregulation of PSMA expression on prostate cancer, which can be targeted with 177Lu-PSMA-617. The ENZA-p trial was also the first to utilize “adaptive dosing” of 177Lu-PSMA-617, with the potential to reduce toxicity, meaning that the agent was only administered for subsequent doses if the patients had evidence of persistent PSMA-positive disease on positron emission tomography (PET) imaging.

 

Results for the primary endpoint of biochemical, prostate-specific antigen (PSA)-progression-free survival (PSA-PFS) showed a strong anticancer effect with the addition of 177Lu-PSMA-617 to the regimen, with a median 13.0 versus 7.8-month PFS for patients treated with the combination versus the enzalutamide group (hazard ratio [HR] = 0.43 (P=0.00001), corresponding to a 57% relative reduction in the risk for recurrence. The results for PSA response rate (RR) also favored the combination, with a 50% and 90% PSA RR observed in 93% versus 68% and 78% versus 37% of patients in the respective groups.  Hematologic toxicity was slightly increased with the combination therapy group, with grade 3 adverse events occurring in 10% and 3% of patients in the respective groups.  Patients in the trial will continue to be followed for PFS as well as overall survival (OS), with results to be reported in 2024.


BOX 1. mCRPC High Risk Features and Eligibility for ENZA-p

Risk Factors for Early Treatment Failure on Enzalutamide

Eligibility Criteria for ENZA-p

  • LDH ≥ULN

  • ALP ≥ULN

  • Albumin <35g/L

  • De novo metastatic disease at diagnosis

  • <3 Years since initial diagnosis

  • >5 Bone metastases

  • Visceral metastases

  • PSA doubling time <84 days

  • Pain requiring opiates >14 days

  • Prior abiraterone

  • mCRPC with PSA rising and >5ng/mL

  •  No chemotherapy for mCRPC

  •   >2 high risk features for enzalutamide failure

  •  Positive PSMA-PET CT (10 or more lesions)

 

MAGNITUDE

Dr Bastos also highlighted the three-year update of the MAGNITUDE Trial presented at ESMO 2023. MAGNITUDE was a phase 3, randomized, double-blind, placebo-controlled study examining the use of 1L niraparib (NIRA), a PARP inhibitor drug, in combination with abiraterone acetate + prednisone (AAP) for patients having mCRPC with homologous recombination repair (HRR) gene mutations (BOX 2), including BRCA 1 or BRCA 2. Most patients in the BRCA+ population of the trial had bone metastases (> 83%) and about 20% in each group had visceral metastases (lung, liver). The previously reported primary analysis from MAGNITUDE demonstrated a statistically significant improvement in radiographic PFS (rPFS) with NIRA + AAP, as compared with placebo (PBO) + AAP, with a HR of 0.53, corresponding to a 47% relative reduction in rPFS (P=0.001). 

 

The final analysis for OS was conducted after a median follow-up of 35.9 months for patients with BRCA+mCRPC and showed a benefit of NIRA over PBO, with a HR of 0.663 (nominal P=0.0237), corresponding to a 34% relative reduction in risk of death in the BRCA+ patients.  Secondary endpoints of time to symptomatic progression (HR = 0.562, nominal P=0.0056) and time to cytotoxic chemotherapy (HR = 0.598, nominal P=0.0192) were also significantly improved with NIRA+AAP versus PBO+AAP.  Deaths that occurred in the trial were attributed to Covid 19 infections and were not considered to be treatment related, and safety results were consistent with the known adverse event profiles of NIRA and other PARP inhibitors.  Dr Bastos noted that, based on the results of MAGNITUDE, the NIRA+AAP regimen is the current standard of care and is presently FDA-approved for use in BRCA+ mCRPC patients.

 

BOX 2. Inclusion Criteria for MAGNITUDE and HRR Biomarker Screening Panel

Inclusion Criteria

HRR Biomarker Prescreening Panel

•       1L mCRPC

•       ≤ 4 months prior AAP allowed for mCRPC

•       ECOG PS 0 or 1

•       BPI-SF worst pain score ≤ 3

ATM, BRCA1, BRCA2,

BRIP1, CDK12, CHEK2,

FANCA, HDAC2, PALB2

 

PSMAFore

Dr Bastos also reviewed findings from the PSMAFore trial, a randomized, open-label study which examined the use of 177Lu‑PSMA‑617 for mCRPC patients who had not received a taxane (e.g., docetaxel) for their disease (taxane-naïve).  He briefly reviewed the mechanism of action for 177Lu‑PSMA‑617, a targeted radiotherapy which binds to PSMA on the surface of prostate cancer cells, after which the radioactive molecule enters the cell, and causes DNA damage and cell death.   In PSMAFore, patients had received a prior therapy with an androgen receptor pathway inhibitor (ARPI) such as enzalutamide and were randomized to second line (2L) treatment with either 177Lu‑PSMA‑617, or a change in their ARPI therapy (e.g., enzalutamide to abiraterone). Crossover to the active treatment arm was allowed in the trial, and the primary endpoint was rPFS, with a key secondary endpoint of OS.  Importantly, Dr Bastos noted that crossover from the comparator treatment (ARPI change) to active treatment (177Lu‑PSMA‑617) occurred at a high rate (84%) in the trial.

 

Results for the primary endpoint showed a significant benefit of 177Lu‑PSMA‑617 over the ARPI change with an HR of 0.41 (P< 0.0001) corresponding to a 59% relative reduction in rPFS (median 12.02 mo vs. 5.59 mo).  There was also a benefit of 177Lu‑PSMA‑617 over ARPI change in terms of overall response rate (ORR) with a rate of 50.7% versus 14.9%, and complete responses occurred in 21.1% versus 2.7% in the respective groups.  There was also a more than doubling in the percentage of patients with PSA declines of 50% or more with the active treatment (57.6% vs. 20.4%), and there were fewer symptomatic skeletal events (10.7% vs. 25.2%).  Health-related quality of life (HRQoL) measures and pain intensity assessments also favored 177Lu‑PSMA‑617 treatment over ARPI change.  With regard to safety, dry mouth was the principal toxicity associated with 177Lu‑PSMA‑617 (57.3% vs. 2.2%), and notably, grade 3 or 4, serious adverse events, and those leading to dose adjustment favored the active treatment versus the comparator arm (BOX 3). Summarizing, Dr Bastos noted the positive results from PSMAFore with significantly prolonged rPFS observed with 177Lu‑PSMA‑617 versus ARPI change for patients as 2L treatment for mCRPC, with improvement in secondary endpoints such as ORR and HRQoL measures and a manageable safety profile.

 

BOX3. Treatment Emergent Adverse Events (AEs) in PSMAFore

 

177Lu‑PSMA‑617

ARPI Change

Grade 3-4 AEs

33.9%

43.1%

Serious AEs

20.3%

28.0%

AEs Leading to Dose Adjustment

3.5%

15.1%

AEs Leading to Discontinuation

5.7%

5.2%

RADICALS-RT

Lastly, Dr Bastos briefly reviewed some updated results from RADICALS-RT, the largest trial examining outcomes following radical prostatectomy (RP) for patients treated with adjuvant (post-surgical) radiotherapy (RT) as compared to salvage RT, performed only after PSA levels start to rise.  The results showed that there was no significant difference in outcomes for key endpoints such as OS and freedom from distant metastases with adjuvant RT after RP versus watching the patient carefully and performing RT only after PSA levels start increasing.  By comparison, there was also a significant difference in safety outcomes (BOX 4), with a higher incidence of AEs such as cystitis, hematuria (blood in the urine), and urethral stricture (narrowing of the urethra), as well as gastrointestinal events such as diarrhea and proctitis with adjuvant versus salvage RT.


BOX 4.  RADICALS-RT: Grade 3 and Higher AEs with Adjuvant Versus Salvage RT


Adjuvant RT

Salvage RT

Gr 3+ Urinary Adverse Events Within 2 Years

Cystitis

Hematuria

Urethral Stricture

 

2%

3%

5%

 

0.7%

0.3%

4%

 

Gr 3+ GI Adverse Events Within 2 Years

Diarrhea

Proctitis

 

1%

1%

 

0.4%

0.4%

 

Speaker Disclosure Information: Dr Bastos reported no disclosures for this presentation.

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