(UroToday.com) The 2022 European Society of Medical Oncology (ESMO) annual meeting featured a prostate cancer session, including a discussant presentation by Dr. Johann De Bono discussing two key studies including “PRESTO: A Phase 3, Open-Label Study of Androgen Annihilation in Patients with High-Risk Biochemically Relapsed Prostate Cancer (AFT-19)” presented by Dr. Rahul Aggarwal and “Biomarker analysis and updated results from the Phase III PROpel trial of abiraterone and olaparib vs abiraterone and placebo as first-line therapy for patients with mCRPC” presented by Dr. Fred Saad. Dr. De Bono notes that from these trials, there are two key questions:
- From the PROpel update: Should we give PARP inhibitors to all mCRPC patients without molecular stratification in the pre-chemotherapy space? In his opinion, based on the available data, PARP inhibition use needs molecular stratification.
- From PRESTO: Should we prescribe apalutamide, or abiraterone and apalutamide, for M0 HSPC with rising PSA, post-radical prostatectomy? In his opinion, there is insufficient data at this point in time, in addition to this being a shrinking disease space due to PSMA PET, as well as the increased utilization of SABR.
As such, these trials have not given us practice changing answers to either question.
Dr. De Bono notes that PRESTO is a randomized phase III, open-label trial in patients with biochemically relapsed prostate cancer and PSA doubling time ≤ 9 months, without distant metastases on conventional imaging (NCT03009981). Patients were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + apalutamide, or ADT + apalutamide + abiraterone acetate plus prednisone, stratified by PSA doubling time (< 3 vs 3–9 months), with post-treatment follow-up:
At the first planned interim analysis (median follow-up 21.5 months), both experimental arms significantly prolonged biochemical progression-free survival compared to the control arm: median 24.9 months for ADT + apalutamide vs 20.3 months for ADT, HR 0.52 (95% CI 0.35–0.77), and median 26.0 months for ADT + apalutamide + abiraterone acetate plus prednisone vs 20.0 months for ADT, HR 0.48 (95% CI 0.32–0.71). With regards to trial design, Dr. De Bono notes that PSA progression free survival is not a surrogate endpoint that can change care, rather that time to M1 disease and overall survival are awaited (but noting that this will take a long time). Additionally, the trial is not powered to address these other analyses. A key question is optimal timing and is this time point (PSA progression free survival) definitely better? Furthermore, he highlighted that apalutamide, and apalutamide + abiraterone acetate improved PSA progression free survival, but the trial was not powered to compare the two treatment arms. Again, time to M1 and OS will be valuable, but the trial was not powered on these outcomes.
Dr. De Bono then discussed PROpel, which is a double-blind, placebo-controlled trial of which 796 patients were randomized 1:1 to olaparib (300 mg twice daily) or placebo, and abiraterone (1000 mg once daily) + prednisone or prednisolone (5 mg twice daily), irrespective of homologous recombination repair gene mutation status:
Dr. De Bono notes that OS in the ITT population was a key secondary endpoint. There was a continued trend towards improved OS with abiraterone + olaparib vs placebo + abiraterone (maturity 40.1%; HR 0.83, 95% CI 0.66–1.03), with the Kaplan-Meier curves showing clear separation between the arms at ~22 months before extensive censoring was observed:
However, the bottom line is there is still no significant OS benefit in the ITT population, with no data regarding DDR and non-DDR tumors. Going back to the basics, Dr. De Bono emphasized that the reason we study PARP inhibition as treatment for mCRPC is because of synthetic lethality. This is results in tumor restricted loss of both alleles (and protein function) causing vulnerability of tumor cells to an intervention that spares normal cells resulting in selective tumor cell cytotoxicity in DDR deficient tumors. The rationale for combining olaparib and abiraterone is that PARP inhibition has been reported to increase activity of novel hormonal agents, and that novel hormonal agents have been reported to induce HRR deficiency and increase susceptibility to PARP inhibition:
Thus, is there really a rationale for PARP inhibition in prostate cancer with DDR? If PAPR inhibition blocked the androgen receptor, there would be decreases in PSA that would have been seen in non-DDR prostate cancer patients. Secondly, if abiraterone/enzalutamide causes HRD, abiraterone + PARP inhibition would hugely increase the response rate, which has not been the case. Thirdly, perhaps there is some other ‘lucky’ serendipitous mechanism of action, such as clearing emerging neuroendocrine clones (ie. RB1, RNASEH2B, BRCA), which may be the case but this may still require molecular stratification.
Dr. De Bono then asked: Should the rPFS data influence our thinking? In PROpel, a benefit was observed with abiraterone + olaparib across HRR mutation (HR 0.50, 95% CI 0.34-0.73) and non-HRR mutation subgroups (HR 0.76, 95% CI 0.60-0.97) based on the first analysis:
However, not all DNA repair defects sensitize to the same extent. Dr. De Bono notes that from the TOPARP-B trial, super-responders have a BRCA2 HOMDEL, which are the hardest alterations to identify, especially in ctDNA and in old FFPE HSPC biopsies [1]:
Dr. De Bono concluded his discussant presentation noting that there are several interpretations of PROpel that may be made in light of TOPARP, PROfound, and MAGNITUDE:
- PARP inhibition has a major impact on outcome in mCRPC with DNA repair defects, especially BRCA altered mCRPC, and especially in BRCA HOMDELs. This is also true for mCRPC with biallelic loss of ATM, PALB2, RAD51, FANCA, and RNASEH2B
- It is likely that a subset in the ‘non-HRR’ subset benefit, but it is also very likely that there are false negative HRR tumors
- We need to better understand PARP inhibitor sensitivity, but we need better biomarker assays for this
- We need to see OS benefit in non-HRR CRPC to recommend PARP inhibition for these patients
Presented By: Johann de Bono, MD, MSc, PhD, FRCP, FMedSci, Royal Marsden NHS Foundation Trust, London, UK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 European Society of Medical Oncology (ESMO) Annual Hybrid Meeting, Paris, FR, Fri, Sept 9 – Tues, Sept 13, 2022.
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Related Content:
PRESTO: A Phase 3, Open-Label Study of Androgen Annihilation in Patients with High-Risk Biochemically Relapsed Prostate Cancer (AFT-19)
Biomarker Analysis and Updated Results from the Phase III PROpel Trial of Abiraterone and Olaparib vs Abiraterone and Placebo as First-Line Therapy for Patients with mCRPC