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PROSTATE CANCER PANEL

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Prostate Cancer Panel

Neeraj Agarwal, MD�Huntsman Cancer Institute, University of Utah

Rana McKay, MD�UC San Diego Health

Michael Morris, MD�Memorial Sloan Kettering Cancer Center

Tanya Dorff, MD�City of Hope

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Where Do We Stand With PARPs?

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Clinical trials of ARSIs plus PARPis

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Saad, et al. NEJM Evidence. 2022; Chi K, et al. JCO. 2023; Agarwal N, et al. Lancet. 2023.

	PROpel (olaparib)	MAGNITUDE (niraparib)	TALAPRO-2 (talazoparib)
Prior NHT in mCSPC	Yes after 12 months of interruption (no abiraterone)	Yes (except abiraterone)	Yes (abiraterone only)
Prior docetaxel in mCSPC	Yes	Yes	Yes
HRR analysis	Tissue or ctDNA / retrospective	100% tissue / prospective	100% tissue / prospective
Primary end point	rPFS (investigator review)	rPFS (central review)	rPFS (central review)
	rPFS, HR (95% CI)
All comers	HR, 0.66 (0.54-0.81)	NR	HR, 0.63 (0.51-0.78)
HRR-negative	HR, 0.76 (0.60-0.97)	HR, 1.09 (0.75-1.59)	HR, 0.66 (0.49-0.91)
HRR-positive	HR, 0.50 (0.34-0.73)	HR, 0.73 (0.56-0.96)	HR, 0.45 (0.33-0.61)
BRCA+	HR, 0.23 (0.12-0.43)	HR, 0.53 (0.36-0.79)	HR, 0.20 (0.11-0.36)
ORR (all comers)	58% vs 48%	60% vs 28% (HRR+ patients only)	62% vs 44%
OS (all comers)	HR, 0.81 (0.67-1.00); P=.054	HR, 0.79 (0.55-1.12); P=.18	HR, 0.89 (0.69-1.14); P=0.35
Regulatory status	BRCA only (FDA) / mCRPC (EMA)	BRCA (FDA and EMA)	Any HRR (FDA) / pending (EMA)

Phase 3 combination trials of PARP inhibitors with novel hormonal therapy (NHT)

Adapted from slide courtesy of Neeraj Agarwal

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Chana Weinstock, MD, FDA, ODAC, April 28, 2023

“We would consider this trial design to be inappropriate today, given emerging data on the strength of BRCA mutations as predictive biomarkers. BRCA status should have been prospectively evaluated, with efficacy results evaluated separately…with stratification or by separate cohorts. This is a significant design flaw…�we would be rewarding poor trial design if we disregarded this issue.”

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FDA, ODAC, April 28, 2023

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LIVE PODCAST:

Current and Future Status

of Radioligand Therapy

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Prostate Cancer Panel

Neeraj Agarwal, MD�Huntsman Cancer Institute, University of Utah

Rana McKay, MD�UC San Diego Health

Michael Morris, MD�Memorial Sloan Kettering Cancer Center

Tanya Dorff, MD�City of Hope

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VISION: Primary and secondary end points

38% reduction in risk of death

50% reduction in risk of SSE

60% reduction in risk of progression or death

9% CR and 42% PR rate

SSE, symptomatic skeletal event.

1. Morris MJ, et al. J Clin Oncol. 2021;39(18_suppl):LBA4. 2. Sartor O, et al. New Engl J Med. 2021;385:1091-1103. 3. Fizazi, et al. ESMO 2021.

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Current practice patterns

Patients selected by PSMA scan results

Six doses of drug administered every 6 weeks regardless of response

No dosimetry

No follow-up with PSMA scans

Treatment terminated by PD on standard scans, but no definition of response

Do any of these actually make sense?

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What is the right way to dose ¹⁷⁷Lu-PSMA?

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PSMAfore: A phase 3, randomized, open-label study

¹⁷⁷Lu-PSMA-617

7.4 GBq (200 mCi) ± 10%

Once every 6 weeks for 6 cycles

ARPI change

abiraterone or enzalutamide

1:1

rPFS by BICR

Follow-up

Stratification factors

Prior ARPI setting (castration-resistant vs hormone-sensitive)
BPI-SF worst pain intensity score (0-3 vs >3)

Crossover allowed upon radiographic progression by BICR

Eligible adults

Confirmed progressive mCRPC
≥1 PSMA-positive metastatic lesion on [⁶⁸Ga]Ga‑PSMA-11 PET/CT and no exclusionary PSMA-negative lesions
Progressed once on prior �second-generation ARPI

Candidates for change in ARPI

Taxane-naive (except [neo]adjuvant �>12 months ago)

Not candidates for PARPi

ECOG performance status 0-1

Sartor, et al. ESMO 2023.

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rPFS and other end points

	¹⁷⁷Lu-PSMA-617 �(n=234)	ARPI change �(n=234)
Events, n	115 (49.1%)	168 (71.8%)
Median rPFS �(95% CI)	12.02 months (9.30, 14.42)	5.59 months (4.17, 5.95)

PSA50: 58% vs 20%

Primary HR: 0.41 (95%CI:0.29, 0.56); p < 0.0001

Updated HR: 0.43 (95%CI:0.33, 0.54)

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Overall survival (note 84% crossover)

Crossover adjusted

ITT

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PSMA-directed RLT may have multiple products in multiple indications �within the next several years

Clinically

localized

disease

Clinical

metastases:

Sensitive to

ADT

Metastatic

disease

treatment:

Second line

Metastatic

disease

treatment:

Fourth line

Metastatic

disease

treatment:

Third line

Rising

PSA

Non-�metastatic

Metastatic

disease

treatment:

First line

PSMA addition

(vipivotide tetraxetan)

PSMAfore (vipivotide tetraxetan)

SPLASH (PNT2002)

ECLIPSE (Lu-177-PSMA I&T))

VISION (vipivotide tetraxetan)

Scher, Morris, et al. JCO. 2016.

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Trial	ClinicalTrials.gov	Phase	N	Regimen
mHSPC
UpFrontPSMA	NCT04343885	II	140	Doce +/− Lu
mCRPC, first line
BULLSEYE, oligomets	NCT04443062	II	58	Lu-PSMA-617 vs ADT
ENZA-p	NCT04419402	II	160	Enza +/− Lu
Alpha/Bet	NCT05383079	I	36	Ra/Lu
mCRPC, second line
LuPARP	NCT03874884	I	52	Lu/olaparib
PRINCE	NCT03658447	I/II	37	Lu/pembro
ARROW	NCT03939689	II	120	Enza +/− MIP 1095 I-131

ADT, androgen deprivation therapy; ARSI, androgen receptor signaling inhibitor; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; RLT, radioligand therapy.

PSMA-based radioligand combination therapies

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PSMA-directed alpha therapeutics: A long time coming

Chakravarty, et al. Am J Nucl Med Mol Imaging. 2018.

Agent	Sponsor	Phase	Targeting Type	ClinicalTrials.gov
CONVO1-alpha (Ac-225)	Convergent	I/II	Antibody	NCT03276572
Cu-64 TLX592	Telix	I (Cupid)	Antibody	NCT04726033
Ac-225 PSMA617	Novartis	I	Small molecule	NCT04597411
Ac-225 PSMA I&T	Fusion	II	Small molecule	NCT05219500

New radioligand targets: hK2, STEAP family, DLL3

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