PARP Inhibitors Make Advances to mCRPC Treatment Paradigm

Maha Hussain, MD

In the treatment landscape of metastatic castration resistant prostate cancer (mCRPC), the introduction of PARP inhibitors as a therapeutic option has led to progress, explained Maha Hussain, MD, in a presentation during the 38th Annual Chemotherapy Foundation Symposium (CFS).

It’s amazing how many clinical trials are ongoing with different PARP inhibitors. There are several phase 3 and phase 2 clinical trials looking at different disease settings,” said Hussain, who is the Genevieve E. Teuton Professor of Medicine in the Division of Hematology Oncology, Department of Medicine, and deputy director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

“Prostate cancer is a very smart disease, and it has a significant intra- and interpatient heterogeneity and variability in the behavior of the disease,” she said. “Clearly, whatever we do has to focus on the totality of the disease biology and individualized care.”

Targeted therapies have only just started to be approved for prostate cancer, Hussain said. Two PARP inhibitors were approved in May 2020 to treat patients with metastatic castration-resistant prostate cancer (mCRPC): rucaparib (Rubrac), which received an accelerated approval, and olaparib (Lynparza), which was granted full approval.

Rucaparib was approved for patients with deleterious germline and/or somatic BRCA-mutated mCRPC based on findings from the single-arm, phase 2 TRITON2 study (NCT02952534). The trial enrolled 115 patients who progressed following treatment with 1 to 2 lines of next-generation androgen receptor–directed therapy and 1 taxane-based chemotherapy. Results showed the objective response rates (ORRs) for evaluable patients based on independent radiology review and investigator assessment were 43.5% (95% CI, 31.0%-56.7%;27 of 62 patients) and 50.8% (95% CI, 38.1%-63.4%; 33 of 65 patients), respectively. ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration. Notably, a higher prostate-specific antigen (PSA) response rate was observed in patients with a BRCA2 alteration. The most frequent grade 3 or higher treatment-emergent adverse event was anemia (25.2%).1

Olaparib is indicated for patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated mCRPC who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga). The approval was based on data from PROfound (NCT02987543), a phase 3 trial of olaparib versus investigator’s choice of enzalutamide or abiraterone acetate. Patients were stratified into 2 cohorts: cohort A (n=245) comprised patients with at least 1 alteration in BRCA1, BRCA2, or ATM, and cohort B (n=142) comprised patients with at least 1 alteration in any of the other 12 prespecified genes.In updated published data, the median duration of overall survival in cohort A was 19.1 months with olaparib versus 14.7 months with control therapy (HR 0.69; 95% CI, 0.50-0.97). In cohort B, the median duration of overall survival was 14.1 months with olaparib versus 11.5 months with control therapy.2

Overall, the treatment was well tolerated, with the most frequent high-grade event being anemia.

“There are many lessons we have learned from PROfound,” said Hussain. “We have screened over 4000 patients internationally. The success rate with NGS [next generation sequencing] testing which was done on all patients was 69%.”

Newly collected tissue, for example, had a higher success rate compared with archival tissue, but if archival tissue is used, better success rates were observed with samples that were less than 5 years prior. Further, success rates in tissue collected from metastatic disease was 63.7% compared with 56.3% in primary samples. This success rate may be because of higher cellularity and tumor content more often seen in metastatic site, Hussain said.

“The critical part of tissue collection, which is something I think is critical when you are speaking with your radiologist if you’re doing a fresh biopsy, is that multiple cord biopsies are necessary,” Hussain said. These samples should then be embedded into one formalin-fixed paraffin-embedded block to maximize the likelihood of successful pathologic review.3

Future Directions

Although these 2 trials and agents have broken through as therapeutic options, Hussain said continued research of PARP inhibitors is necessary. Questions remain about these therapies, especially related to the best timing of administering the therapy, the relation to other life-prolonging treatments, sensitivity of the disease to PARP inhibitors and other treatments, tumor heterogeneity, and how to overcome mechanisms of resistance.

Investigators of the phase 2 CheckMate 9KD trial (NCT03338790) are exploring the efficacy of rucaparib in combination with nivolumab (Opdivo), docetaxel (Taxotere) plus prednisone, or enzalutamide in patients with mCRPC. The trial is currently active, but not recruiting. Additionally, data from the phase 2 TRIUMPH trial (NCT03413995) will determine if rucaparib leads to lowering of PSA levels in men with metastatic hormone sensitive prostate cancer and who have an inherited mutation in a gene involved in repairing DNA damage.

Olaparib is being explored both in combination and as monotherapy across trials. “We developed a randomized clinical trial that is asking the question, ‘If a patient has canonical HRR mutations, specifically in BRCA 1/2 or ATM does it make a difference if the get olaparib, abiraterone [acetate], or the combination [of the olaparib, abiraterone acetate, and prednisone]?’” Hussain said. The BRCAAway trial (NCT03012321) is almost fully enrolled, she added.

Investigators of the phase 3 PROpel study (NCT03732820) will evaluate the efficacy of olaparib in combination with abiraterone acetate versus abiraterone acetate alone as a first-line therapy for mCRPC. Planned subgroup analysis will include HRR gene status.

Other PARP agents being studied include niraparib (Zejula), talazoparib (Talzenna), and pamiparib (BGB-290). Niraparib is being investigated in several studies, including as a monotherapy (NCT02854436), in combination with apalutamide (Erleada) or abiraterone acetate (BEDIVERE; NCT02924766), and in combination with radium-223 (Xofigo) (NiraRad; NCT03076203).

Talazoparib is being studied in combination with enzalutamide (TALAPRO-2; NCT03395197) and in combination with avelumab (Bavencio) (NCT03330405). Pamiparib is being investigated in combination with temozolomide (Temodar) in a phase I study (NCT03150810).

_References:

_{1. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. Published online August 14, 2020. doi:10.1200/JCO.20.01035}

_{2. Hussain MHA, Mateo J, Fizazi K, et al; PROfound Trial Investigators. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. Published online September 20, 2020. doi:10.1056/NEJMoa2022485}

_{3. Hussain MHA. Optimizing use of PARP inhibition for prostate cancer. Presented at: 38th Annual CFS®. November 4-6, 2020.}