“Although PARP inhibitor treatment has demonstrated radiographic and PSA responses in patients with BRCA alterations (4–8), the data presented here offer compelling evidence that response to PARP inhibitors is limited in men with mCRPC harboring an ATM, CDK1/2, or CHEK2 alteration."
Although limited radiographic or prostate-specific antigen (PSA) responses were observed with rucaparib (Rubraca) as treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who harbored alterations in ATM, CDK1/2, or CHEK2, men with alterations in other DNA damage repair (DDR)-associated genes may benefit from the PARP inhibitor, according to the phase 2 TRITON2 clinical trial.
Radiographic responses were observed in 10.5% of patients with an ATM alteration, 0% of patients with a CDK1/2alteration, 11.1% of patients with a CHEK2 alteration, and PSA responses were observed in 4.1%, 6.7%, and 16.7% of these patients, respectively. Patients who had alterations in other DDR genes, such as PALN2, FANCA, BRIP1, andRAD51B had responses to the PARP inhibitor.
“Although PARP inhibitor treatment has demonstrated radiographic and PSA responses in patients with BRCA alterations (4–8), the data presented here offer compelling evidence that response to PARP inhibitors is limited in men with mCRPC harboring an ATM, CDK1/2, or CHEK2 alteration,” wrote lead author Wassim Abida, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center. “These data provide an optimistic outlook for the treatment of prostate cancer with other DDR gene alterations, such as PALB2.”
The open-label TRITON study was conducted across 144 centers in a dozen countries. Overall, 78 patients were enrolled who had a non-BRCA DDR gene alteration, which included ATM (n = 49), CDK12 (n = 15), CHEK2 (n = 12), and other DDR genes (n = 14). Other alterations in DDR genes included FANCA (n = 4), NBN (n = 4), BRIP1 (n = 2), PALB2 (n = 2), and RAD51, RAD51B, or RAD54L (n = 1 each).
Overall, 2 patients (with an ATM alteration 10.5%) had a confirmed partial radiographic response, which included 1 patient who had a co-occurring CHEK2 alteration. The responses were ongoing at 1.8 and 2.0 months from the date of radiographic response. The same 2 patients with the ATM alteration had a confirmed PSA response (4.1%), as well. Among patients in the ATM group, the 6-month clinical benefit rate was 28.6%, and the 12-month clinical benefit rate was 16.7%, regardless of measurable disease status.
The ATM alterations among this group of patients who achieved responses were detected through cell-free DNA (cfDNA) screening, so investigators noted the potential for homozygous loss of another DDR gene among these patients.
Among patients in the CDK1/2 cohort, there were no confirmed radiographic responses, but 1 patient had a confirmed PSA response (6.7%), which lasted 1.8 months. The 6-month clinical benefit rate was 20.0%, and the 12-month rate was 7.1%. The patient who had a PSA response had 2 distinct alterations in the CDK1/2 gene, which were presumed to be biallelic and identified in the cfDNA and tissue.
Only 1 patient in the CHEK2 cohort had a confirmed partial radiographic response (11.1%), and this patient also had a co-occurring ATM alteration. Additionally, 2 patients had a PSA response (16.7%), including the 1 patient with a radiographic response. Both patients had ongoing PSA responses of at least 3.7 and 0.9 months. The 6-month clinical benefit rate was 37.5%, and no patients were receiving treatment at 12 months.
The CHEK2 alterations were identified through cfDNA screening as well among the 2 patients with a PSA response, whereas 1 alteration was somatic and the second was germline. The patient with the germline alteration was found to have a somatic BRCA2 alteration, according to a tissue analysis after enrollment.
Among patients with other DDR gene alterations, 4 had a confirmed radiographic response (28.6%), and 5 had a PSA response (35.7%). Both of the patients with a PALB2 alteration achieved PSA responses, and 1 patient had a partial radiographic response ongoing for at least 3.9 months. One other patient had a 47% reduction in tumor volume, but this patient did not undergo a follow-up scan for confirmation as of the cutoff. One patient with a FANCA alteration had a complete radiographic response, as well as a PSA response that remained ongoing. One patient with a BRIP1 alteration had a partial radiographic and PSA response, which both remained ongoing. A partial radiographic and PSA response also remained ongoing in the patient with a RAD51B alteration.
Treatment-emergent adverse events (TEAEs) of any grade were observed in 76 patients (97.4%). The most frequent TEAEs, which occurred in at least 20% of the patients, were fatigue, nausea, decreased appetite, anemia, constipation, vomiting, and diarrhea. Thirty-nine patients experienced grade 3 or greater TEAEs (50.0%), which included anemia, asthenia, or fatigue, and thrombocytopenia. No TEAEs of myelodysplastic syndrome or acute myeloid leukemia were observed.
TEAEs led to treatment interruption in 24 patients (43.6%), which was most commonly due to asthenia or fatigue in 10 patients (43.6%) and anemia in 8 patients (10.3%). TEAEs also led to dose reductions in 21 patients (26.9%), which were most commonly due to asthenia or fatigue in 6 patients (7.7%), anemia in 3 patients (3.8%), and thrombocytopenia in 3 patients (3.8%).
A total of 4 patients had discontinued treatment due to a TEAE, which included asthenia or fatigue in 1 patient, decreased appetite in 1 patient, hematuria in 1 patient, and postoperative respiratory failure in 1 patient. One death occurred (1.5%) due to intestinal ischemia, which was considered unrelated to rucaparib.
Overall, PARP inhibitors have demonstrated promising responses in heavily pretreated patients with mCRPC who harbor a BRCA alteration. However, alterations in non-BRCA DDR genes are not as established as biomarkers for response to PARP inhibitors like rucaparib. This study demonstrated that non-BRCA DR gene alterations may predict response to rucaparib treatment. However, the sample size of this study remains small for patients with CDK1/2, CHEK2, and other non-BRCA DDR gene alterations. Tissue and plasma test results were also not available for all patients in this study.
“Further work is needed to determine whether PARP inhibitors provide disease stabilization in patients with an ATM or CDK12 alteration or whether there are other genomic characteristics for patients who achieve a response, and to better define the subset of other DDR gene alterations that confer sensitivity to PARP inhibitors in the setting of mCRPC,” the authors concluded.
This study led to the FDA approval of rucaparib on May 15, 2020 for the treatment of adult patients with a deleterious BRCA mutation-associated mCRPC who had received prior treatment with androgen receptor-directed therapy and a taxane-based chemotherapy. The continued approval of this agent is contingent on the verification of clinical benefit from confirmatory trials.
Abida W, Campbell D, Patnaik A, et al. Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study [Published Online February 21, 2020]. Clinical Cancer Research. doi: 10.1158/1078-0432.CCR-20-0394