Therapeutic biomarkers in metastatic castration-resistant prostate cancer: does the state matter?

Figures & data

Table 1. PARP inhibitor monotherapies.

		Olaparib		Rucaparib		Niraparib		Talazoparib
Approval for mCRPC		EMA: BRCAm after ARSI FDA: HRRm^1 after ARSI		EMA: Not approved FDA: BRCAm after ARSI & taxane		EMA: Not approved FDA: Not approved		EMA: Not approved FDA: Not approved
Trial (Phase) [Ref]		PROfound (3) [74]		TRITON3 (3) [86]	TRITON2 (2) [84]	GALAHAD (2) [87]		TALAPRO-1 (2) [88]
Prior treatment lines		ARSI: ≥ 1^A^,^B,^C Taxane: allowed^A^,^B,^C		ARSI: 1^C Taxane: allowed^A	ARSI: 1 or 2^A^,^B,^C Taxane: 1^C	ARSI: ≥ 1^C Taxane: ≥ 1^C		ARSI: ≥ 1^C Taxane: ≥ 1^A^,^C
Main endpoint		rPFS		rPFS	ORR	ORR		ORR
Biomarker group		BRCAm^α	Non-BRCAm^2	BRCAm^δ	Non-BRCAm^3,^ζ	BRCAm	Non-BRCAm^4	BRCAm	Non-BRCAm^5^,^θ
Zygosity		Mono- and biallelic		Mono- and biallelic		Biallelic or germline		Mono- and biallelic
PSA50	n/total	58/94	15/151^β	111/201^ε	9/78	61/142	4/81	39/61	5/43
	Fraction	61.7%	9.9%	55.0%	11.5%	43.0%	4.9%	63.9%	11.6%
ORR	n/total	25/57	5/84^γ	37/82	6/43	26/76	5/47	28/61	3/43
	Fraction	43.9%	6.0%	45.1%	14.0%	34.2%	10.6%	45.9%	7.0%
rPFS	n	102	156	201	78	142	81	61	43
	Months	9.8	Min. cohort B: 4.8 Max. ATM: 5.4	11.2	Min. CDK12: 3.7 Max. other: 11.6^η	8.08	3.71	11.2	Min. other: 1.8 Max. PALB2: 5.6

Based on Slootbeek PHJ, Overbeek JK, Ligtenberg MJL, et al. PARPing up the right tree; an overview of PARP inhibitors for metastatic castration-resistant prostate cancer. Cancer Lett. 2023 2023/09/07/:216367. https://doi.org/10.1016/j.canlet.2023.216367.

Prior treatment lines:

^A For mCSPC.

^B For nmCRPC.

^C For mCRPC.

Gene panels (genes in bold are genes in which aberrations were identified):

¹ ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L.

² ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L.

³ ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L.

⁴ ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2.

⁵ ATM, ATR, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C.

Manner of data collection:

^α Data from exploratory analysis from the abstract by De Bono et al. [90].

^β Calculated by subtracting Cohort A from the overall population of de Bono et al. [74] and adding the ATM mutated population from the abstract by De Bono et al. [90].

^γ Calculated by adding ATM mutated population from the abstract by De Bono et al. [90] to Cohort B, calculated by Stopsack et al. [82].

^δ ATM subgroup from TRITON3 had a PSA50 rate of 2/69 (3%, not separately presented in the article), ORR rate of 0/24 (0%) and rPFS of 8 months.

^ε A PSA50 response rate of 55% was reported by Fizazi et al. This could either imply 110 or 111 patients with a PSA50.

^ζ Counted from figure 2 from Abida et al. [84].

^η Not presented by Abida et al. [84], data retrieved from Study Results section of NCT page (NCT02952534). Median rPFS: ATM 5.3 months; CDK12 3.7 months; CHEK2 9.4 months; Other genes 11.6 months.

^θ Counted from table 2 from de Bono et al. [88].

ARSI, androgen receptor signaling inhibitor; BRCAm, BRCA mutated; EMA, European Medicines Agency; FDA, Food and Drug Administration; HRRm, homologous recombination repair mutated; mCSPC, metastatic castration-sensitive prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; n, number of patients; nmCRPC, non-metastatic CRPC; ORR, objective radiologic response; PSA50, ≥50% prostate specific antigen decline; rPFS, radiologic progression-free survival.

Table 2. PARP and AR co-inhibition.

Trial name		PROPEL [104]			MAGNITUDE			TALAPRO-2			CASPAR
PARPi, ARSI		Olaparib, Abiraterone			Niraparib, Abiraterone			Talazoparib, Enzalutamide			Rucaparib, Enzalutamide
NCT		NCT03732820			NCT03748641			NCT03395197			NCT04455750
Prior treatment lines		Abiraterone: Not allowed Enzalutamide: Allowed^A*^,^B Taxane: Allowed^A			Abiraterone: Allowed^B* Enzalutamide: Allowed^A,^B Taxane: Allowed^A			Abiraterone: Allowed^A Enzalutamide: Not allowed Taxane: Allowed^A			Abiraterone: Allowed^A,^B Enzalutamide: Not allowed Taxane: Allowed^A, B
Main endpoint		rPFS by investigator			rPFS by BICR			rPFS by BICR			rPFS by BICR & OS
Genetic subgroups		HRRm: 226/796 (28%)^1; BRCAm: 85/226 (38%)			HRRm: 423/423 (100%)^2; BRCAm: 225/423 (53%)			HRRm: 169/805 (21%)^3; BRCAm: 60/169 (36%)			^4
Treatment arm		PARPi + ARSI	ARSI	HR (95% CI) / OR [95% CI]	PARPi + ARSI	ARSI	HR (95% CI) / p-value	PARPi + ARSI	ARSI	HR (95% CI) / p-value	Results are not yet available
HRRm		111/399 (2%)	115/397 (29%)		212/212 (100%)	211/211 (100%)		85/402 (21%)	84/403 (21%)
ORR	Unselected	94/161 (58%)	77/160 (48%)	1.60 [1.02–2.53]	All patients were HRRm			74/120 (62%)	58/132 (44%)	p = 0.005
	HRRm	Not reported			55/92 (60%)	23/82 (28%)	p < 0.001	Not reported
	BRCAm	Not reported			29/56 (52%)	15/48 (31%)	p = 0.04	Not reported
rPFS ^α	Unselected	24.8 months	16.6 months	0.66 (0.54–0.81)	All patients were HRRm			Not reached	21.9 months	0.63 (0.51–0.78)
	HRRm	Not reached	13.9 months	0.50 (0.34–0.73)	16.5 months	13.7 months	0.73 (0.56–0.96)	27.9 months	16.4 months	0.46 (0.30–0.70)
	BRCAm	Not reached ^β	8.4 months ^β	0.23 (0.12–0.43)	16.6 months	10.9 months	0.53 (0.36–0.79)	Not reported
	HRRp	24.1 months	19.0 months	0.76 (0.60–0.97)	Closed due to futility: HR 1.09 (0.75–1.57)			Not reached	22.1 months	0.66 (0.49–0.91)

Based on Slootbeek PHJ, Overbeek JK, Ligtenberg MJL, et al. PARPing up the right tree; an overview of PARP inhibitors for metastatic castration-resistant prostate cancer. Cancer Lett. 2023 2023/09/07/:216367. https://doi.org/10.1016/j.canlet.2023.216367.

Prior treatment lines:

^A* For (m)CSPC but only without progression during treatment and stopped 12 months before randomization.

^A For (m)CSPC.

^B* For mCRPC with maximum treatment duration of ≤4 months prior to randomization.

^B For nmCRPC.

^C For mCRPC.

Gene panels:

¹ ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Including 18 patients with unknown HRRm status.

² ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2.

³ ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, PALB2, RAD51C, NBN, MLH1, MRE11A, and CDK12. Including patients with unknown HRRm status.

⁴ A subgroup analysis will be performed on patients with pathogenic alterations in BRCA1, BRCA2, and PALB2.

Manner of data collection:.

^α rPFS reported according to the main endpoint of the study.

^β Not in main article. Data from the presentation by Dr. Saad at ESMO 2022 [105].

ARSI, Androgen receptor signaling inhibitor; BICR, blinded independent central review; BRCAm, BRCA mutated; CI, confidence interval; HR, hazard ratio; HRRm, homologous recombination repair mutated; HRRm, homologous recombination repair proficient; NCT, ClinicalTrials.gov identifier; OR odds ratio; PARPi, PARP inhibitor; rPFS, radiographic progression-free survival.

Table 3. Platinum-based chemotherapy response by homologous recombination repair status.

		Mota et al. [114]			Slootbeek et al. [115]			Pomerantz et al. [104]
Prior therapies		Taxane naïve: none PARPi refractory: none			Taxane naïve: 2 out of 30 patients PARPi refractory: 3 out of 14 HRRm patients			Taxane naïve: 133 out of 144 patients PARPi refractory: none presumed^α
Type platinum agent and combination		Platinum agent		Combined with	Platinum agents		Combined with	Platinum agent	Combined with
		Carboplatin Cisplatin		Monotherapy: 33% Taxane: 64% Etoposide: 3%	Carboplatin: 100%		Monotherapy: 11% Docetaxel: 86% Cyclophosphamide: 3%	Carboplatin: 100%	Docetaxel: 100%
Genetic subgroup		BRCA2m	HRRm^1	HRRp	BRCA2m	HRRm^2	HRRp	BRCA2m^β	BRCA2p^β
PSA50	n/total	4/6	8/16	5/40	7/7	10/14	5/16	6/8	23/133
	Fraction	66.7%	50.0%	12.5%	100%	71.4%	31.3%	75.0%	17.3%
ORR	n/total	NR	NR	NR	7/7	7/12	3/14	NR	NR
	Fraction	NR	NR	NR	100%	58.3%	21.4%	NR	NR
OS	n	6	16	48	7	14	16	8	133
	Months	8.4	9.0	7.8	21.1	8.4	7.0	18.9	9.5

The genes in bold are found in patients enrolled in the corresponding trials.

¹ ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MRE11, NBN, PALB2, RAD50, RAD51 and RAD51C.

² ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BARD1, BRIP1, CDH1, CDK12, CHEK1, CHEK2, ERCC2, ERCC4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, PARP1, PARP2, PARP3, PPP2R2A, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L and RPA1.

^α Due to inclusion period from 2001 to 2015. Prior treatment with PARP inhibitors not stated in the article.

^β Germline carriers.

BRCA2m, BRCA2 mutated (including homozygous loss); BRCA2p, BRCA2 proficient; HRRm, homologous recombination repair mutated; HRRp, homologous recombination repair proficient; n, number of patients; NR, not reported; ORR, objective radiologic response; OS, overall survival; PARPi, PARP inhibitor; PSA50, ≥50% prostate specific antigen decline.

Table 4. Response om immune checkpoint inhibitor by homologous recombination repair status.

	n, total	HRR proficient		HRR mutated		p-value
		n	Fraction	n	Fraction
PSA50	205	11/163	6.7%	9/42	21.4%	0.008
ORR	178	11/143	7.7%	7/35	20.0%	0.054
PFS6	59	12/46	26.1%	8/13	61.5%	0.022

Genes associated with HRR per included trial. The genes in bold are found in patients enrolled in the corresponding trials.

KEYNOTE-199^a [141]: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L.

CheckMate 650 [142]: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D and RAD54L.

STARVE-PC^b [143]: all DDR related genes according to Mateo et al. [80]. Genes identified: ATM, BRCA2, ERCC4, FANCM.

^a The KEYNOTE-199 study did not provide detailed information on which genes were altered.

^b The limitation of this study is the range of sequencing panels used in which several HRR-related genes are missing: CancerSELECT-R^TM 88 (n = 3), CancerSELECT^TM 125 (n = 1), CancerSELECT^TM 203 (n = 6), PlasmaSELECT^TM 64 (n = 4), Foundation® Panel (n = 1).

HRR, homologous recombination repair; n, number of patients; ORR, objective radiologic response; PFS6, progression-free survival of ≥6 months; PSA50, ≥50% prostate specific antigen decline.

Table 5. Response of mismatch repair deficient patients on immune checkpoint inhibitors.

	Type of ICI	Pts analyzed for MMRd	MMRd pts		With ICI	PSA50		PSA99		ORR
			Pts	Fraction	Pts	Pts	Fraction	Pts	Fraction	Pts	Fraction
Abida et al. [64]	Anti-PD-L1 (n = 4), anti-PD-1 (n = 7)	1346	32	2.4%	11	6/11	54.5%	4/11	36.4%	4/8	50.0%
Antonarakis et al. [62]	Anti-PD-1	584	13	2.3%	4	2/4	50.0%	NR	NR	3/4	75.0%
Graham et al. [63]	Anti-PD-1	NR	27	NR	17	8 /15	53.3%	5/15*	33.3%	NR	NR
Barata et al. [182]	Anti-PD-1	460	15	3.3%	9	4/9	44.4%	3/9	33.3%	3/5	60.0%
Sena et al. [183]	Anti-PD-1	NR	65	NR	19	11/17	64.7%	4/17*	23.5%	NR	NR
Total						31/56	55.4%	16/52*	30.8%	10/17	58.8%

* Estimated.

ICI, immune checkpoint inhibitors; MMRd, mismatch repair deficient; NR, not reported; ORR, objective radiologic response; PD-1, programmed cell death protein 1; PD-L1, Programmed cell death protein ligand 1; PSA50, ≥50% prostate specific antigen decline; PSA90, ≥90% prostate specific antigen decline; Pts, number of patients.

de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091–2102. doi: 10.1056/NEJMoa1911440.

 PubMed Web of Science ®Google Scholar

Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719–732. doi: 10.1056/NEJMoa2214676.

 PubMed Web of Science ®Google Scholar

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. Clin Cancer Res. 2020;26(11):2487–2496. doi: 10.1158/1078-0432.CCR-20-0394.

 PubMed Web of Science ®Google Scholar

Smith MR, Scher HI, Sandhu S, et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022;23(3):362–373. doi: 10.1016/S1470-2045(21)00757-9.

 PubMed Web of Science ®Google Scholar

de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250–1264. doi: 10.1016/S1470-2045(21)00376-4.

 PubMed Web of Science ®Google Scholar

Bono JSD, Matsubara N, Penel N, et al. Exploratory gene-by-gene analysis of olaparib in patients (pts) with metastatic castration-resistant prostate cancer (mcrpc): PROfound. J Clin Oncol. 2021;39(6_suppl):126–126. doi: 10.1200/JCO.2021.39.6_suppl.126.

 PubMedGoogle Scholar

Stopsack KH. Efficacy of PARP inhibition in metastatic castration-resistant prostate cancer is very different with non-BRCA DNA repair alterations: reconstructing prespecified endpoints for cohort B from the phase 3 PROfound trial of olaparib. Eur Urol. 2021;79(4):442–445. doi: 10.1016/j.eururo.2020.09.024.

 PubMed Web of Science ®Google Scholar

Pomerantz MM, Spisák S, Jia L, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer. 2017;123(18):3532–3539. doi: 10.1002/cncr.30808.

 PubMed Web of Science ®Google Scholar

Saad F, Armstrong A, Thiery-Vuillemin A, et al. 1357O biomarker analysis and updated results from the phase III PROPEL trial of abiraterone (abi) and olaparib (ola) vs abi and placebo (pbo) as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2022;33:s1160. doi: 10.1016/j.annonc.2022.07.1945.

 Google Scholar

Mota JM, Barnett E, Nauseef JT, et al. Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations. J Clin Oncol Precis Oncol. 2020;4:355–366. doi: 10.1200/po.19.00346.

 PubMed Web of Science ®Google Scholar

Slootbeek PH, Duizer ML, van Der Doelen MJ, et al. Impact of DNA damage repair defects and aggressive variant features on response to carboplatin-based chemotherapy in metastatic castration-resistant prostate cancer. Int J Cancer. 2021;148(2):385–395. doi: 10.1002/ijc.33306.

 PubMed Web of Science ®Google Scholar

Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38(5):395–405. doi: 10.1200/JCO.19.01638.

 PubMed Web of Science ®Google Scholar

Sharma P, Pachynski RK, Narayan V, et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. 2020;38(4):489–499. e3. doi: 10.1016/j.ccell.2020.08.007.

 PubMed Web of Science ®Google Scholar

Boudadi K, Suzman DL, Anagnostou V, et al. Ipilimumab plus nivolumab and DNA-repair defects in Ar-V7-expressing metastatic prostate cancer. Oncotarget. 2018;9(47):28561–28571. doi: 10.18632/oncotarget.25564.

 PubMedGoogle Scholar

Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–1708. doi: 10.1056/NEJMoa1506859.

 PubMed Web of Science ®Google Scholar

Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5(4):471–478. doi: 10.1001/jamaoncol.2018.5801.

 PubMed Web of Science ®Google Scholar

Antonarakis ES, Shaukat F, Isaacsson Velho P, et al. Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur Urol. 2019;75(3):378–382. doi: 10.1016/j.eururo.2018.10.009.

 PubMed Web of Science ®Google Scholar

Graham LS, Montgomery B, Cheng HH, et al. Mismatch repair deficiency in metastatic prostate cancer: response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. doi: 10.1371/journal.pone.0233260.

 PubMed Web of Science ®Google Scholar

Barata P, Agarwal N, Nussenzveig R, et al. Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA. J Immunother Cancer. 2020;8(2):e001065. doi: 10.1136/jitc-2020-001065.

 PubMed Web of Science ®Google Scholar

Sena LA, Fountain J, Isaacsson Velho P, et al. Tumor frameshift mutation proportion predicts response to immunotherapy in mismatch repair-deficient prostate cancer. Oncologist. 2021;26(2):e270–e278. doi: 10.1002/onco.13601.

 PubMed Web of Science ®Google Scholar