(UroToday.com) At the second prostate cancer session at the 2020 Annual Meeting of the Society of Urologic Oncology (SUO), Dr. Maha Hussain presented the results of the PROfound study, Study of Olaparib (Lynparza) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study), which demonstrated the superiority of olaparib, a poly (adenosine diphosphate-ribose) polymerase inhibitor, for treatment of metastatic castrate-resistant prostate cancer (mCRPC).

After a brief discussion of the ToPARP trial and some of the rationale which lead to the genesis of the PROfound study, Dr. Hussain launched into a discussion of the trial itself. In this trial, published in the New England Journal of Medicine in May 20201 with an update in the same journal in September2, patients with the following characteristics were enrolled:

There were no restrictions based on ECOG status, volume or location of metastases, or prior taxane therapy.

Patients with mutations in BRCA1, BRCA2, ATM were called and cohort A and were the primary population for the analysis.

These patients were randomized to olaparib 300mg twice-daily vs the physician's choice of abiraterone or enzalutamide. The primary endpoint was imaging-based progression-free survival in cohort A based on blinded central review.

Overall the results were resoundingly positive, with olaparib showing superiority in progression-free survival (7.4 mo vs 3.6 mo, HR 0.34 0.25-0.47, P<0.001), the median time to pain progression (HR 0.44 0.22-0.91, P <0.02), andoverall survival (19.1 months vs 14.7 mo, HR 0.69 9.50-0.97 P =0.02)in cohort A. This overall survival difference is particularly impressive given an 81% cross over from the control to the olaparib arm after progression in these patients.

Results in the full population were similar, as were results from numerous prespecified subgroup analyses, including patients with and without prior taxane use, bone only and visceral metastases, and baseline ECOG score of 0 and 1.

This data lead to the United States Federal Drug Administration (FDA) to approve olaparib for patients with mCRCP with deleterious or suspected deleterious germline or somatic homologous recombination repair mutations who have progressed on enzalutamide or abiraterone. This recommendation was similarly adopted in theNational Comprehensive Cancer Network (NCCN) guidelines.

(Similar approval was given to rucaparib based on the TRITON2 study, though this was limited to tumors with deleterious BRCA mutations and men previously treated with taxane chemotherapy.)

As Dr. Daniel Spratt argued in his counterpoint, however, this approval may be overly broad.

When analyzing patients by which genes were altered, the 95% CI of patients with BRCA2 mutations was the only one not to cross 1 (HR 0.21 0.12-0.32) for progression-free survival despite there being similar numbers of patients with ATM and CDK12 mutations. The signal of benefit was generally much stronger in BRCA mutations for both OS and PFS, with very little signal of benefit in the remaining patients, so it may be wise to limit clinical use to patients with these mutations.

Dr. Spratt also pointed out that there now exists a large body of evidence suggesting there is very little benefit in using abiraterone after progression on enzalutamide (or similar) and vice versa. Thus, for the 44.7% (173/387) patients who received docetaxel only, and certainly for the 34% who had received no prior chemotherapy (133/387), olaparib cannot be said to have been compared to the current standard of care in this trial.

Thus even for patients with BRCA mutations, which seem to confer the most favorable responses to olaparib, it remains very much unclear whether olaparib should be chosen before exhausting the numerous alternative available therapies.

Presented by: Maha H.A. Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine, Division of Hematology-Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine

Daniel Spratt, MD, Professor, Laurie Snow Research Professor of Radiation Oncology, University of Michigan

Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia PA, @mcstroth duringthe 2020 Society of Urologic Oncology Annual Meeting December 2-5, 2020 Washington, DC

References:

1. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. doi: 10.1056/NEJMoa1911440. Epub 2020 Apr 28. PMID: 32343890.

2. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. Published online September 20, 2020:NEJMoa2022485.

Related ContentPatients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Can Be Preselected to Maximize Benefit of Olaparib - Maha Hussain

Continued here:
SUO 2020: New Second Line Therapy for mCRPC: PARPi: Results from the PROfound Study - UroToday

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