ASCO GU 2021: CtDNA testing can effectively determine Olaparib's effect on desopathic prostate cancer (PROfound study)

In metastatic degenerative resistant prostate cancer (mCRPC), errogen recombinant repair (HRR) pathline gene mutations (e.g. BRCA1 and BRCA2) have a stronger disease invasiveness and higher mortality rate.
these gene mutations are more sensitive to adenosine polyphosphate (PARP) inhibitors, and the efficacy of PARP inhibitor Olapa in patients with mCRPC with HHR gene mutations has been confirmed in PROfound studies.
early data supported the use of the PARP inhibitor olaparib (Olapali) in TOPARP-A trials, and found improvements in progress-free survival and overall survival rates in men treated extensively with mCRPC.
similar results were observed in phase II TOPARP-B trials, which were subsequently demonstrated in the Phase III PROfound trial, which demonstrated an improvement in the progress-free and overall survival of men with the same recombinant repair defective mCRPC after treatment with acetic acid abitronate or enzalutamide.
compared to the new oral androgen axis-targeted drugs, the metastasis time of non-metastatic desopathic prostate cancer treated with olapani or the metastatic metastasis of metastatic desopathic prostate cancer.
evidence that the trial requires comogen recombinant repair (HRR) gene changes, usually determined by tumor tissue testing.
, ctDNA testing may also allow HHR status to be detected.
in the poster highlights of the 2021 ASCO GU Cancer Symposium: A summary of the Prostate Cancer Conference, Dr Matsubara and colleagues conducted a retrospective assessment of ctDNA to identify changes in male BRCA1, BRCA2 and ATM in the PROfound trial.
PROfound's approach has previously been reported and published, but in general, men with metastatic degenerative resistance prostate cancer have progressed when they have taken acetic absinthion or erythromycin in non-metastatic degenerative resistance prostate cancer or non-metastatic degenerative prostate cancer.
raised metastatic de-sensitive prostate cancer.
allow patients who have previously been exposed to yew alkanes.
then used a FoundationOne CDx-based study to identify changes in one of the 15 pre-specified genes involved in the same recombination repair (BRCA 1/2, ATM, BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L).
PROfound study was a Phase III. randomized controlled study that included mCRPC patients with 1-15 HRR gene mutations who had previously been treated with second-generation anti-male drugs (enzaluamine, abitron).
are divided into two queues based on biomarker-driven strat threes.
patients with queue A carry at least one of the BRCA1, BRCA2, or ATM gene mutations, and Queue B carries at least one of the other 15 gene mutations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L).
two cohort patients were randomly assigned to the Olapali group (300mg 2 times/day) or the control group (160mg 1 time/day) and the 1000mg-a-day 1st and 1000mg-per-day (5mg 2x/day) control groups, which could be crossed to the Olapali group if the disease progressed.
in each biomarker layer, random groupings are layered based on previous use of yew alkane drugs and measurable disease burden (according to THESIST 1.1 standard).
the main endpoint of queue A is imaging progress-free lifetime (rPFS), with OS as the secondary endpoint, which also includes random grouping to the time of second progress or death.
OS Final Analysis deadline is March 20, 2020.
results were presented, and at the time of final analysis, 148 (60%) of the 245 patients in Queue A had died, meeting pre-set criteria.
OS in the Olapali group was 19.1 months, and the control group was 14.7 months (HR, 0.69; 95% CI: 0.50-0.97; P=0.02).
67% of the control group crossed to the Olapali group after progress, and after correction HR was 0.42 (95% CI:0.19-0.91).
100 (70%) of the 142 patients in OS Queue B died after graph 1 Queue A OS Figure 2 Queue A corrected cross factors.
OS in the Olapali group was 14.1 months, compared with 11.5 months in the control group (HR, 0.96; 95% CI: 0.63-1.49).
the cross factors, HR is 0.83 (95% CI:0.11-5.98).
based on preclinical data, it was not possible to verify the role of PPP2R2A as an HHR gene, and in patients with PPP2R2A gene mutations, opapari did not observe a survival advantage compared to the control group.
In an ex post-expedited exploratory analysis, excluding these patients from queue B, HR was 0.79 (95% CI:0.51-1.25), and the mid-OS in the Olapali and control groups was 14.2 months and 10.8 months, respectively.
3 Queue B OS Figure 4 Queue B corrected cross-factors in the overall OS population, 248 (64%) of the 387 patients died, and the mid-OS in the Opalli and control groups was 17.3 months and 14.0 months (HR, 0.79; 95% CI:0.61-1.03), respectively.
the cross factors, HR is 0.55 (95% CI:0.29-1.06).
sensitivity analysis, excluding patients with PPP2R2A gene mutations, HR was 0.76 (95% CI:0.58-1.00), and the mid-OS in the Olapali and control groups was 17.4 months and 13.6 months, respectively.
5 Overall Population OS (Queue A plus Queue B) Figure 6 After the overall population corrects cross factors, OS reports the value of ctDNA testing at this meeting.
, the authors examined patients who agreed and provided queue A plasma samples (tested positive for BRCA/ATM changes through tissue).
ctDNA samples were sequenced on FMI, using plasma samples collected during screening in PROfound, and BRCA1, BRCA2 (BRCA) and ATM were changed through TheUndationOne Liquid CDx analysis.
consistent with the main endpoint of the study, the non-imaging progression-free lifetime (rPFS) was assessed by a blind independent central evaluation (BICR) in patients who were positive for ctDNA through a strated number of rank tests.
also assessed other secondary efficacy endpoints (objective mitigation rate (ORR), overall survival rate (OS)).
Of the 245 patients in Queue A, 181 (73.9%) agreed and provided plasma samples for ctDNA testing, of which 139/181 (76.8%) reported ctDNA results (mutation positive or mutation negative), of which 42 patients were unable to pass the test due to insufficient DNA production or failed testing techniques.
BRCA/ATM changes were identified in 111/139 (79.9%) patients, and the remaining 28 patients did not report BRCA/ATM mutations in ctDNA tests, due to a lack of ctDNA shedding from the tumor or ctDNA levels below detection sensitivity.
demographics, baseline characteristics and proportions of BRCA/ATM ctDNA changes in the population and the entire queue A, BRCA1, BRCA2, and ATM mutations.
patients with ctDNA BRCA/ATM changes received rPFS in patients who received Olaparib compared to the anti-androgen conversion chosen by the researchers.
the authors conclude that ctDNA testing in mCRPC patients is both feasible and largely consistent with tissue-based HR mutation status assessments.
, the response to Olaparib was similar between patients identified as having BRCA/ATM changes based on ctDNA and patients in the entire queue A.