Recent PARP Inhibitor Data in Prostate Cancer

Case: A 65-Year-Old Man With Prostate Cancer

January 2018

Initial Presentation

• A 65-year-old man was diagnosed with localized prostate cancer
• Biopsy revealed adenocarcinoma of the prostate gland, Gleason score 7 [4+3]
• PSA 15.7 ng/mL
• Baseline staging: T3bN1M0 with right seminal vesicle and pelvic lymph node involvement

Initial Treatment

• He undergoes radical prostatectomy with PLND
  • PSA nadir of 0.4 ng/mL post-surgery
  • Gleason 7 (4 + 3) confirmed
  • Positive surgical margins
  • Baseline staging confirmed – AJCC Stage IVA

February 2019

Follow-Up Notes

• Serum PSA, 38 ng/mL; ALP, 289 IU/L
• PSMA PET CT:
  • Metastatic retroperitoneal LNs outside resection field
  • Abdominal nodes
  • Bone mets in ribs and thoracic spine
• Genetic testing: BRCA2 mutation-positive

Additional Treatment

• Abiraterone + prednisone initiated
• Improved pain, PSA, and ALP

October 2019

Follow-Up Notes

• Patient reported bone pain
• Laboratory testing revealed rising PSA and ALP (serum PSA, 350 ng/mL; ALP, 2500 IU/L)
• Imaging showed radiologic progression
• ECOG PS 1
• PSMA PET CT: increased uptake in retroperitoneal and abdominal LNs

mCRPC Treatment

• Treated with docetaxel x4 cycles and denosumab
  • Serum PSA, 38 ng/mL; ALP, 289 IU/L
  • Reporting bone pain increased in back, now reporting pain in hip area
• Bone scan and CT scan:
  • Enlargement of retroperitoneal and abdominal LNs
  • Additional bone mets noted in pelvic region

Transcript:

Daniel J. George, MD: It’s important to recognize that PROpel was a confirmation phase 3 study from an earlier proof of concept phase 2 study. They’re not the only 2 studies of PARP inhibitors in metastatic castrate-resistant prostate cancer. There is a study with enzalutamide and talazoparib called TALAPRO-2, which had a very similar design to the PROpel study. It also took an all-comers population, but it did prespecify patients who had homologous recombination repair [HRR] defects and BRCA defects from those who had non-HRR mutated tumors and separated those populations. They were stratified by that and, again, randomized to either enzalutamide and placebo or enzalutamide plus talazoparib. They were able to demonstrate a significant radiographic progression-free survival benefit for the intention-to-treat population, but a greater benefit associated with patients who had BRCA mutations and even those who had homologous recombination repair defects. That has led to its approval by the FDA for a similar indication in metastatic castrate-resistant prostate cancer of patients with BRCA or homologous recombination repair defect to receive enzalutamide in combination with talazoparib.

Then there was another full approval based on the TRITON3 study, which was a phase 3 study of rucaparib, a third PARP inhibitor. This was studied in patients with metastatic castrate-resistant prostate cancer who had received a prior novel hormonal agent and docetaxel chemotherapy. In this study, patients were randomized to best supportive care, whether that was another novel hormonal agent, chemotherapy, or rucaparib, and they were able to demonstrate a benefit associated with rucaparib in patients who had BRCA or a homologous recombination repair defects. It was specifically BRCA1/2 and ATM that their population focused on. So specifically looking at those patients, they were able to demonstrate a benefit both in radiographic progression-free survival and overall survival.

These are important trends we’re seeing now of the benefits in this selected population of patients from the addition of PARP inhibitors, whether it be after a novel hormonal agent as a single agent, or in the case of talazoparib and olaparib, in combination with a novel hormonal agent in this first-line castrate-resistant prostate cancer setting. It opens the door for our patients to benefit from these drugs earlier and potentially take advantage of some synergy between the novel hormonal agent, androgen receptor [AR] pathway inhibition and the role the androgen receptor plays on DNA repair as well as PARP inhibition, which the androgen receptor works through for DNA repair and which can trap PARP and prevent any additional AR signaling from repairing DNA in these patients. It’s a great opportunity to maximize the benefit associated with PARP inhibition in these selected patients.

Transcript edited for clarity.