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Ref Type

Journal Article

PMID

(32086346)

Authors

Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, Voog EG, Bryce AH, McDermott R, Ricci F, Rowe J, Zhang J, Piulats JM, Fizazi K, Merseburger AS, Higano CS, Krieger LE, Ryan CJ, Feng FY, Simmons AD, Loehr A, Despain D, Dowson M, Green F, Watkins SP, Golsorkhi T, Chowdhury S

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	26	11	2020 Jun 01	2487-2496	Clin Cancer Res

URL

Abstract Text

Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations.TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline).TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration [ATM (n = 49), CDK12 (n = 15), CHEK2 (n = 12), and other DDR genes (n = 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM [2/19 (10.5%) and 2/49 (4.1%), respectively], CDK12 [0/10 (0%) and 1/15 (6.7%), respectively], or CHEK2 [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B.In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (e.g., PALB2) may benefit from PARP inhibition.See related commentary by Sokolova et al., p. 2439.

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Molecular Profile	Treatment Approach
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATM inact mut	prostate cancer	no benefit	Rucaparib	Phase II	Actionable	In a Phase II trial (TRITON2), activity of Rubraca (rucaparib) was limited in the cohort of patients with metastatic castrate-resistant prostate cancer harboring an ATM mutation presumed to be inactivating, with a radiographic response rate of 10.5% (2/19, including 1 patient with co-occurring CHEK2 alteration) and PSA response rate of 4.1% (2/49), and no radiographic responses in 11 patients with biallelic alterations in ATM or 11 patients with germline ATM alterations (PMID: 32086346; NCT02952534).	32086346
CDK12 inact mut	prostate cancer	no benefit	Rucaparib	Phase II	Actionable	In a Phase II trial (TRITON2), activity of Rubraca (rucaparib) was limited in the cohort of patients with metastatic castrate-resistant prostate cancer harboring a CDK12 mutation presumed to be inactivating, with no confirmed radiographic responses in 10 evaluable patients and a PSA response in 1 patient with biallelic CDK12 alterations in the overall population of 15 patients, and a clinical benefit rate of 20% (3/15) at 6 months and 7.1% (1/14) at 12 months (PMID: 32086346; NCT02952534).	32086346
CHEK2 inact mut	prostate cancer	no benefit	Rucaparib	Phase II	Actionable	In a Phase II trial (TRITON2), activity of Rubraca (rucaparib) was limited in the cohort of patients with metastatic castrate-resistant prostate cancer harboring a CHEK2 mutation presumed to be inactivating, with a radiographic partial response in 1 patient who had a co-occurring ATM alteration out of 9 evaluable patients, and PSA response rate of 16.7% (2/12), and a clinical benefit rate of 37.5% (3/8) at 6 months, with no patients remaining on treatment at 12 months (PMID: 32086346; NCT02952534).	32086346
BRIP1 inact mut	prostate cancer	predicted - sensitive	Rucaparib	Case Reports/Case Series	Actionable	In a Phase II trial (TRITON2), 1 of 2 patients with metastatic castrate-resistant prostate cancer harboring deleterious BRIP1 alterations demonstrated a PSA response and partial radiographic response after treatment with Rubraca (rucaparib), which were ongoing at the time of visit cutoff (PMID: 32086346; NCT02952534).	32086346
FANCA inact mut	prostate cancer	predicted - sensitive	Rucaparib	Case Reports/Case Series	Actionable	In a Phase II trial, 1 of 4 patients with metastatic castrate-resistant prostate cancer harboring deleterious FANCA alterations demonstrated a PSA response and complete radiographic response after treatment with Rubraca (rucaparib), which were ongoing at the time of visit cutoff (PMID: 32086346; NCT02952534).	32086346
PALB2 inact mut	prostate cancer	predicted - sensitive	Rucaparib	Case Reports/Case Series	Actionable	In a Phase II trial (TRITON2), 2 of 2 patients with metastatic castrate-resistant prostate cancer harboring deleterious PALB2 alterations demonstrated a PSA response after treatment with Rubraca (rucaparib), with one of those patients demonstrating partial radiographic response that was ongoing 3.9 months, and the other a 47% reduction in tumor volume (PMID: 32086346; NCT02952534).	32086346
RAD51B rearrange	prostate cancer	predicted - sensitive	Rucaparib	Case Reports/Case Series	Actionable	In a Phase II trial (TRITON2), a patient with metastatic castrate-resistant prostate cancer harboring a RAD51B rearrangement demonstrated a PSA response and partial radiographic response after treatment with Rubraca (rucaparib), which were ongoing at the time of visit cutoff (PMID: 32086346; NCT02952534).	32086346

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