Potential Use of PARP Inhibitors for First-Line Treatment of mCRPC

EP: 1.Case Presentation: A 64-Year-Old Man with Metastatic Prostate Cancer

EP: 2.Typical Presentations of Metastatic Prostate Cancer and Risk of Disease Progression

EP: 3.The Utility of Genetic Testing in Patients with Prostate Cancer

EP: 4.Mutations in HRR-Related Genes in Prostate Cancer

EP: 5.Available Treatment Options for Chemotherapy-Naïve mCRPC

EP: 6.Olaparib Safety and Efficacy Data from the PROfound Trial

EP: 7.A Urologist’s Treatment Selection for Metastatic Prostate Cancer

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EP: 8.Potential Use of PARP Inhibitors for First-Line Treatment of mCRPC

EP: 9.Current Challenges and Future Directions in Metastatic Prostate Cancer

Case Overview:

Initial Presentation (Jan 2017)

A 64-year-old man is found to have a firm bilateral prostate nodule of 1.8 mm on his routine physical exam

Clinical workup

PSA 109.1 ng/mL

Family history of prostate cancer (father, uncle)

Transrectal ultrasound (TRUS)-guided biopsy of the prostate confirms advanced adenocarcinoma of the prostate and Gleason score of 8 (4 + 4)/Grade Group 4

MRI is negative for pelvic LN involvement but positive for one 1.1-cm mediastinal supraclavicular LN (T2bN0M1a)

His ECOG PS is 1

Germline multigene testing of biopsy specimen revealed a BRCA2 mutation

Initial Treatment (starting Feb 2017)

Patient was started on leuprolide and abiraterone; scheduled for physical exam, PSA assessment, and imaging every 3 months.

By the second follow-up visit (6 months after initiating treatment; August 2017), PSA levels declined to 2.1 ng/mL and prostate nodule size was 1.4 mm.

Patient’s disease remained stable through August 2018 (18 months of treatment).

21- and 24-month Follow-up Notes (November 2018, February 2019)

Patient’s PSA levels increased to 46.9 ng/mL in 11/2018 and 73.7 ng/mL in 2/2019.

MRI revealed that the size of the existing positive LN increased to 1.3 cm, and revealed a new, faintly positive 0.9-cm para-aortic LN.

Given the recent findings and the patient’s known BRCA2 mutation status, the patient and clinician decide to initiate olaparib 300 mg BID.

Neal Shore, MD, FACS: Could PARP inhibitors potentially be used earlier in the treatment of mCRPC [metastatic castration-resistant prostate cancer] alongside other first-line treatments? Yes, there are the olaparib and the niraparib trials that were recently described at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], PROpel and MAGNITUDE, respectively. Fred Saad, [MD,] presented the PROpel data; the publication is pending. Kim Chi, [MD,] presented the MAGNITUDE trial data, and Tia Higano, [MD, FACP,] was the discussant. I would strongly encourage my colleagues, these were both successful studies. They both met their primary end points; survival data are still pending. What they demonstrated was PROpel, in an all-comers population, combining olaparib and abiraterone did better in first-line mCRPC versus abiraterone. For MAGNITUDE, in a population enriched for BRCA2, patients receiving niraparib and abiraterone versus abiraterone alone also had a marked improvement in their rPFS [radiographic progression-free survival] benefit. That was specifically in HRR [homologous recombination repair]-mutated patients, or what we call biomarker positive. That is really important. You can go to the links, read those. The publications are both still pending. There’s not yet regulatory approval for that combination, but I think it’s very encouraging and very promising.

Also, at ASCO GU was the first-line triplet combination known as the ARASENS trial, combining ADT [androgen deprivation therapy], docetaxel, and darolutamide versus ADT, docetaxel, and placebo. That was a successful study presented by Matthew Smith, [MD, PhD,] and largely impacting patients with high-volume disease, demonstrating the value of triplet therapy as opposed to combination couplet therapy in patients with newly diagnosed, high-volume mCSPC [metastatic castration-sensitive prostate cancer].

In these trials, does enrollment depend on HRR mutation status? Clearly it did for MAGNITUDE. Not so much so for PROpel, but many want to see the breakdown of the HRR-positive versus negative mutational status. I think you’ll see that forthcoming in subsequent meetings, congresses, particularly ASCO in 2022 and potentially at ESMO [European Society for Medical Oncology] 2022 as well.

Transcript edited for clarity.