Prostate cancer, BRCA-mutated

Page editor		Section editor
	Laura S. Graham, MD University of Colorado Anschutz Medical Campus Aurora, CO LauraGrahamMD		Ali Raza Khaki, MD Stanford University Palo Alto, CA arkhaki

2 regimens on this page 3 variants on this page

Note: this page has regimens which are specific to prostate cancer that is BRCA-mutated. Please see the main prostate cancer page for other regimens.

Metastatic castration-resistant

Olaparib monotherapy

Regimen variant #1, 300 mg BID

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
de Bono et al. 2020 (PROfound) ESMO-MCBS (3)	4/2017-11/2018	Phase 3 (E-RT-switch-ooc)	Physician's choice of: 1a. Abiraterone 1b. Enzalutamide	Seems to have superior OS1 (secondary endpoint) Median OS: 19.1 vs 14.7 mo (HR 0.69, 95% CI 0.50-0.97)

¹Reported efficacy is for patients in Cohort A in the 2020 update.

Prior treatment criteria

• Progression on abiraterone or enzalutamide

Biomarker eligibility criteria

• Cohort A: 1+ alterations in BRCA1, BRCA2, or ATM
• Cohort B: 1+ alterations in BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L

Targeted therapy

• Olaparib (Lynparza) 300 mg PO twice per day

Continued indefinitely

Regimen variant #2, 400 mg BID

Study	Evidence
Kaufman et al. 2014 (Study 42)	Phase 2, <20 pts in subgroup
Mateo et al. 2015 (TOPARP-A)	Phase 2

Biomarker eligibility criteria

• Study 42: Germline BRCA1/2 mutations and had progression on hormonal and one systemic therapy
• TOPARP-A: Patients who were found to have homozygous deletions, deleterious mutations, or both in DNA-repair genes were much more likely to respond to olaparib

Targeted therapy

• Olaparib (Lynparza) 400 mg PO twice per day

Continued indefinitely

References

1. Study 42: Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01078662
2. TOPARP-A: Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01682772
3. PROfound: de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. link to original article contains dosing details in manuscript link to supplementary appendix PubMed NCT02987543
   1. Update: Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Özgüroğlu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J; PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357. Epub 2020 Sep 20. link to original article PubMed

Rucaparib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Abida et al. 2020 (TRITON2) ESMO-MCBS (3)	2017-NR	Phase 2 (RT)

Targeted therapy

• Rucaparib (Rubraca) 600 mg PO twice per day

Continued indefinitely

References

1. TRITON2: Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, Sautois B, Vogelzang NJ, Bambury RM, Voog E, Zhang J, Piulats JM, Ryan CJ, Merseburger AS, Daugaard G, Heidenreich A, Fizazi K, Higano CS, Krieger LE, Sternberg CN, Watkins SP, Despain D, Simmons AD, Loehr A, Dowson M, Golsorkhi T, Chowdhury S; TRITON2 investigators. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol. 2020 Nov 10;38(32):3763-3772. Epub 2020 Aug 14. link to original article contains dosing details in abstract link to PMC article PubMed NCT02952534