But First, the Biology of Inhibition of PARP (Poly (ADP-Ribose) Polymerase): Briefly.
In the myriad of cell divisions random mistakes are made in the faithful transcription of DNA into daughter cells. Some errors are of no consequence (passenger mutations), others can change the behavior of genes often with deleterious effects, such as inducing cancer or increasing its aggressiveness. Of interest in this Commentary are mutations that derange the normal function of the ~14 members of the BRCA family of DNA repair genes, notably BRCA 1, 2 and ATM. The BRCA genes are the first-line of defense repairing damaged DNA. When mutations impair the repair function of BRCA genes, the second line of defense for DNA repair is the PARP mechanism which insures the fidelity of DNA replication. The combination of BRCA malfunction and PARP inhibition (technically termed “synthetic lethality”) is cell death. An estimated 6%-9% of men carry a germline (inherited) mutation in BRCA 2, and a total of ~11% have other BRCA family mutations amenable to olaparib therapy. The first PARP inhibitor to be FDA approved (January 2018) was olaparib (Lynparza).
[PCa Commentary Vol. #160 addresses who should be tested and how to get tested for BRCA mutations] PCa Commentary #160 – Gene Mutations in the BRCA Family and PARP Inhibition Therapy. (control+click link to follow or visit https://www.prostatecancerfree.org/prostate-cancer-news)
This Commentary presents the trial results that support the current use of olaparib and introduces the PROpel trial which tested moving the combination olaparib and abiraterone to first-line treatment of metastatic castration-resistant prostate cancer (mCRPC).
Early Studies of Olaparib for Treatment of men with BRCA Mutations:
Groundbreaking research by Mateo and colleagues (NEJM 2015)) established a role for the PARP inhibitor, olaparib in the treatment of men with mCRPC harboring mutations in the genes BRCA 1, 2 and ATM. In their small study of 16 heavily treated men all 7 men with BRCA2 mutations and 4 of 5 with mutated ATM responded. Overall survival for biomarker-positive patients compared to those biomarker-negative was 13.8 vs 7.5 months.
The PROfound trial confirmed the effectiveness of olaparib therapy in men with mCRPC (Hussain, Mateo et al., NEJM 12/2022). This study enrolled 387 men who had progressed to metastatic disease after standard ADT (i.e., Lupron, which was continued). Olaparib was compared to either Zytiga or Xtandi, depending on which of the two drugs had been used following progression on ADT.
One comparison was of men who had mutations in BRCA 1, 2 and ATM. The radiographic progression-free survival (rPFS) was 5.8 months for olaparib vs 3.5 for Zytiga or Xtandi. Median overall survival at early analysis was 19.1 vs 14.0 months, respectively.
A second comparison assessed the outcome of treatment for the entire study group and included men with BRCA 1, 2 and ATM mutations and those with one or more of the 12 other mutated genes in the BRCA family. The median overall survival was 17.5 (BRCA positive) vs 14.3 months, (BRCA negative). An important finding, however, was that response to olaparib was seen in all men with any BRCA family mutations. The PROfound trial results are the basis for the NCCN approval for olaparib for men with mCRPC with mutations in the BRCA family after progression on Xtandi or Zytiga.
The PROpel trial — Advancing the PARP Inhibitor Olaparib Combined with Abiraterone to First-Line Therapy for mCRPC
As of December 2022, the FDA granted priority review of olaparib/abiraterone/prednisone as first line therapy for mCRPC for men with and without mutations in the BRCA family.
** But first, what underlying biology supports this combination?
Preclinical research identified that PARP activity is necessary for an activated androgen receptor (AR) to promote cancer proliferation, and that inhibition of PARP decreases AR function. Additionally, it is thought that abiraterone may decrease the activity of some DNA repair genes. It was theorized that the combination of olaparib and abiraterone could synergistically impair AR function, yielding an anti-tumor effect, and could benefit men regardless of mutations in the BRCA family.
The PROpel Trial:
This trial tested the combination olaparib/abiraterone/prednisone as a first-line regimen compared with abiraterone/placebo in men with mCRPC. (“Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer,” Clark et al. NEJM Evidence, June 2022). The 796 men had progressed to metastatic disease after initial ADT: ~87% had disease spread to bone and ~32% to distant lymph nodes. ADT was continued after progression. Although mutations in the BRCA family were not required for eligibility, all men were assessed for the mutational status of 14 genes in the BRCA family by FoundationOne on biopsy specimens or circulating tumor DNA. The aggregate prevalence of mutated BRCA2 was ~9% and mutated BRCA1 ~1-2%.
**Findings: (Reported at about 50% of estimated study maturity)
1) Median rPFS was 27.6 months for olaparib/abiraterone vs 16.4 months for abiraterone/placebo, a 34% improvement.
2) The olaparib/abiraterone regimen benefited men with mutations and those without as compared to the abiraterone/placebo group: a 50% betterment for those men with mutations, but also a significant benefit of 24% for those lacking mutations.
3) The overall survival data was immature, but early analysis showed a trend favoring abiraterone and olaparib in combination.
4) The commonest adverse events exceeding 20% in the combined regimen were anemia (46%), fatigue (37%) and nausea (28%). Grade > 3 anemia was more commonly seen in the combination regimen 15.1% vs 5.3%, and pulmonary embolism occurred in 6.5% v 1.8%. No difference in cardiovascular adverse events occurred between groups.
**Study conclusion: “The overall results of PROpel demonstrate the clinical benefit of olaparib in combination with abiraterone in the first-line treatment of a broad … population of patients with mCRPC” unselected for BRCA family mutations.
If approved by the FDA upon complete review, the combination of olaparib/abiraterone/prednisone will move to the pole position in the treatment of men with mCRPC regardless of their BRCA family mutational status.text inline or in the module Content settings. You can also style every aspect of this content in the module Design settings and even apply custom CSS to this text in the module Advanced settings.