Next Steps in PARP Inhibitor Targeted Approaches for Prostate Cancer: Single Agents and Combinations

In a presentation at the 2022 Great Debates and Updates in Genitourinary Oncology meeting, Maha Hussain, MD, FACP, FASCO, Northwestern Medicine Feinberg School of Medicine, Chicago, IL, discussed poly ADP ribose polymerase (PARP) inhibitor targeted approaches for the treatment of metastatic castration-resistant prostate cancer.

There are several PARP inhibitors in prostate cancer that have been evaluated and the top 4 are currently undergoing active investigation: olaparib, rucaparib, niraparib, and talazoparib.

The PROfound trial was a randomized, phase 3 trial that evaluated the role of olaparib in patients with metastatic castration-resistant prostate cancer. Patients were stratified to two distinct cohorts based on alterations (BRCA1 or BRCA2 or ATM [group 1] or other alterations [group 2]) and randomized to olaparib vs the control. Olaparib resulted in a clinically significant improvement in radiographic progression-free survival (PFS; hazard ratio [HR] for disease progression or death 0.34, P <.001).

Rucaparib was evaluated in the TRITON2 study in patients with both BRCA and non–BRCA alterations. In patients with BRCA, rucaparib resulted in clinically significant improvements in response based on measurable disease response, declines in prostate-specific antigen (PSA), and a radiographic PFS. Although, this improvement was not as profound in patients with non–BRCA alterations.

In 2020, the FDA approved both olaparib and rucaparib for patients with metastatic castration-resistant prostate cancer. Olaparib was approved for patients who had deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations that had progressed after prior treatment with enzalutamide or abiraterone. Rucaparib was approved for patients with deleterious BRCA mutations (germline or somatic) who had prior treatment with androgen receptor-directed therapy and a taxane-based chemotherapy.

The 2 other agents have undergone testing and preliminary data has been reported. Niraparib has demonstrated response rates, PSA decline, and CTC conversions in patients with metastatic castration resistance prostate cancer with biallelic DDR mutations. Talozoprib has also demonstrated evidence of activity in this patient population, as seen in the TALAPRO-1 study.

“Now clearly developing combination treatment is an important strategy in all of oncology and certainly prostate cancer is one of them. There is scientific rationale for cotargeting androgen receptor (AR) signaling and PARP,” explained Dr Hussain, who presented ongoing efforts aimed at exploring these combination approaches.

Most ongoing phase 3 trials are exploring PARP inhibitors in combination with AR-targeted therapy, including the PROpel (olaparib and abiraterone), TALAPRO-2 (talazoparib and enzalutamide), CASPAR (rucaparib plus enzalutamide), and MAGNITUDE (niraparib and abiraterone).

There are several other trials ongoing looking at other combinations. “Certainly, there is a fair amount of biological and preclinical data supporting the rationale to combine with immune therapy, in addition to a variety of other biological pathways.”

The combination studies Dr Hussain decided to focus on were the PROpel trial and MAGNITUDE trial. The PROpel trial is a randomized, phase 3 trial evaluating olaparib and abiraterone vs placebo and abiraterone in the first-line treatment of metastatic castration-resistant prostate cancer. The primary end point is radiographic PFS by investigator assessment, demonstrating a 34% risk production of progression or death in favor of the combination (HR 0.66; P <.0001).

The MAGNITUDE trial is a randomized, phase 3 trial evaluating niraparib combined with abiraterone and prednisone as first-line treatment of metastatic castration-resistant prostate cancer. This trial was designed to have a futility analysis and patients who did not have homologous recombination repair were terminated because there was no advantage reported in adding niraparib to abiraterone and prednisone for these patients.

In patients who were biomarker positive, specifically those with BRCA1 or BRCA2 alterations, there were significant improvements in radiographic PFS by central review (HR 0.53; P = .0014) and assessed by investigator (HR 0.50; P = .0006) with the combination arm vs the placebo arm.

“With this data, I think we will need to wait for the final publications for these 2 trials to really dissect all of the information and better understand how this will impact the standard of care, and of course, whether this will lead to FDA approvals as something to be awaited,” said Dr Hussain.

“I think it's really delightful that we have entered the era of precision medicine in metastatic castration resistant prostate cancer with the emergence of PARP as a key therapeutic target,” she concluded.

Source:
Hussain M. Next Steps in PARPi Targeted Approaches: Single Agents and Combinations. Presented at: 2022 Great Debates and Updates in Genitourinary Oncology; March 9-11, 2022; virtual. Accessed March 30, 2022.