Press Release: Novartis Pluvicto(TM) shows clinically meaningful and highly statistically significant rPFS benefit in patients with PSMA-positive metastatic ...

-- Phase III PSMAfore trial with Pluvicto(TM) met its primary endpoint of

radiographic progression-free survival (rPFS) with a HR of 0.411;

Pluvicto more than doubled median rPFS to 12.0 months per updated

analysis*1

-- Pluvicto also showed improved quality of life compared to daily oral ARPI,

along with improvements in other clinically meaningful efficacy

endpoints1

-- Overall survival (OS) data interpretation at second interim analysis was

confounded by 84% crossover1; PSMAfore continues to collect OS data

-- Novartis is investigating a broad portfolio of RLTs in advanced cancers

including breast, colon, neuroendocrine, lung, pancreatic and prostate

and is investing in production capacity to continue meeting global

patient needs

Basel, October 23, 2023 -- Novartis today presents data from the Phase III PSMAfore trial at the 2023 European Society for Medical Oncology (ESMO) Congress. Data presented at the Presidential Symposium showed that Pluvicto(TM) (lutetium ((177) Lu) vipivotide tetraxetan) met its primary endpoint with a clinically meaningful and statistically significant benefit in radiographic progression-free survival (rPFS) in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) after treatment with androgen receptor pathway inhibitor (ARPI) therapy, compared to a change in ARPI(1).

Efficacy endpoint Pluvicto vs. change in ARPI

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Radiographic progression-free HR 0.41 (95% CI: 0.29, 0.56;

survival *(a) p<0.0001)

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Median rPFS* 12.0 vs. 5.6 months

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>=50% decline in prostate-specific 57.6% vs. 20.4%

antigen levels

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Time to symptomatic skeletal HR 0.35 (95% CI: 0.22, 0.57)

event (SSE)(a)

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Objective response rate (ORR)(b) 50.7% vs. 14.9%

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Duration of response (DOR)(b) 13.6 vs. 10.1 months

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FACT-P score(a) HR 0.59 (95% CI: 0.47, 0.72)

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Brief Pain Inventory-Short Form HR 0.69 (95% CI: 0.56, 0.85)

(BPI-SF)(a)

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Prespecified crossover-adjusted HR 0.80 (95% CI: 0.48, 1.33)

overall survival(a)

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Unadjusted OS(a) (84% crossover) HR 1.16 (95% CI: 0.83, 1.64)

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(a) Hazard Ratio (95% Confidence Interval). Functional Assessment of Cancer Therapy-Prostate

(b) In patients with measurable disease at baseline in soft tissue per RECIST v1.1.

"The rPFS data are impressive and the treatment effect is comparable with what was observed in the VISION trial," said Dr. Oliver Sartor, PSMAfore Co-Principal Investigator, Chairman of the Trial Steering Committee and adjunct professor in the Department of Urology at Tulane University School of Medicine, New Orleans, LA, one of the many sites where the trial was conducted. "We look forward to a future where Pluvicto may be a viable therapy for patients in need of alternative, earlier options."

"These promising results from PSMAfore could change the treatment paradigm for advanced prostate cancer by allowing patients to potentially avoid or delay taxane-based chemotherapy, which carries a heavy burden of side effects," said Jeff Legos, Executive Vice President, Global Head of Oncology Development at Novartis. "While data collection for overall survival continues, the consistency of the benefit observed on other clinically meaningful efficacy endpoints, together with improved quality of life and favorable safety profile, show the potential of Pluvicto for taxane-naïve patients with mCRPC."

The trial met its primary endpoint of rPFS(2) with a 59% reduction in the risk of radiographic disease progression in patients with Pluvicto versus a change of ARPI(1). Using a data cut off with a median of 8.6 months longer study follow-up, an updated rPFS analysis (HR 0.43; 95% CI: 0.33, 0.54) demonstrated a consistent clinical benefit in patients with Pluvicto versus a change in ARPI, more than doubling time to radiographic disease progression (12.0 months vs. 5.6 median months)(1).

Patients on Pluvicto also showed improved quality of life, maintaining their FACT-P total score for 3 months longer than a change in ARPI (7.5 vs. 4.3 months), with a delay in worsening pain (BPI-SF) of 5.0 versus 3.7 months(1). Other clinically meaningful efficacy endpoints also favored Pluvicto, with a PSA decline of at least 50% being >2.5X more frequent with Pluvicto than with a change in ARPI(1).

At the second interim OS analysis with 45% of events, the pre-specified crossover-adjusted OS analysis demonstrated a hazard ratio of 0.80 (95% CI: 0.48, 1.33)(1). The unadjusted intent-to-treat OS analysis was confounded as 84% of patients who discontinued ARPI due to radiographic progression crossed over to receive Pluvicto(1). The trial will continue to assess OS, with the next interim OS analysis expected in 2024.

The trial demonstrated a favorable safety profile with 6 cycles of Pluvicto(1) :

Adverse events (AEs) Pluvicto vs. change in ARPI(a)

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Grade 3--4 33.9% vs. 43.1%

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Serious 20.3% vs. 28.0%

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Leading to dose-adjustment 3.5% vs. 15.1%

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Leading to discontinuation 5.7% vs. 5.2%

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(a) In patients who experienced >=1 adverse event.

The most frequently reported all-grade AEs for Pluvicto were primarily Grade 1--2 and included dry mouth (57.3%), asthenia (31.7%), nausea (31.3%), anemia (24.2%) and fatigue (22.9%)(1).

Currently, patients diagnosed with metastatic prostate cancer have a 5-year survival rate of approximately 30%(3) and there remains an urgent need for treatment options for patients who have disease progression despite the current standard of care(4-) (7).

*Pluvicto met its primary endpoint of rPFS at the primary analysis based on centrally confirmed rPFS events with an October 2022 data cut off(1). The updated exploratory rPFS analysis was based on the latest data cut off of June 2023 and only nominally significant(1).

About the PSMAfore Study

PSMAfore (NCT04689828) is a Phase III, open-label, multi-center, 1:1 randomized study comparing the efficacy and safety of Pluvicto to a change in ARPI (abiraterone or enzalutamide) in patients with PSMA-positive mCRPC who have not been exposed to a taxane-containing regimen(8). Patients enrolled must have progressed only once after receiving a second-generation ARPI (abiraterone, enzalutamide, darolutamide or apalutamide)(8).

Patients randomized to the change in the ARPI arm were allowed to crossover to receive Pluvicto upon confirmation of radiographic progression by blinded independent central review (BICR). There were 469 participants enrolled in the study(8).

The primary endpoint is rPFS, defined as the time from randomization to radiographic progression by PCWG3-modified RECIST v1.1 (as assessed by BICR) or death(8). The key secondary endpoint of OS is defined as the time from date of randomization until the date of death due to any cause(8). The pre-specified crossover-adjusted OS analysis was performed using the rank-preserving structural failure time (RPSFT) model to adjust for crossover(8).

About Pluvicto(TM) (lutetium ((177) Lu) vipivotide tetraxetan)

Pluvicto is an intravenous radioligand therapy (RLT) combining a targeting compound (a ligand) with a therapeutic radionuclide (a radioactive particle, in this case lutetium-177)(9,10). After administration into the bloodstream, Pluvicto binds to target cells, including prostate cancer cells that express PSMA, a transmembrane protein(9,10). Once bound, energy emissions from the radioisotope damage the target cells and nearby cells, disrupting their ability to replicate and/or triggering cell death(10).

Pluvicto is approved in the U.S., the E.U. and other countries to treat adults with a type of advanced cancer called PSMA-positive mCRPC and who have already been treated with other anticancer treatments (ARPI and taxane-based chemotherapy)(11-1) (5). These regulatory decisions are supported by the results from the pivotal Phase III VISION trial, where Pluvicto met both primary endpoints of OS and rPFS, reducing the risk of death by 38% and the risk of radiographic progression or death by 60% compared to standard of care(9).

As part of our goal to move into earlier stages of disease, we have two additional Phase III studies to evaluate Pluvicto in earlier lines of treatment for PSMA-positive prostate cancer: PSMAddition (NCT04720157) is ongoing in the metastatic hormone-sensitive setting and PSMA-DC (NCT05939414) in the oligometastatic setting is in preparation. More information on these studies may be found at www.clinicaltrials.gov.

Novartis and Prostate Cancer

With more than 1.4 million new cases and 375,000 deaths in 2020 alone, prostate cancer is the most frequently diagnosed cancer in men in 112 countries -- more than half the world(1) (6).

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October 23, 2023 10:30 ET (14:30 GMT)