Background

Cancer diagnosis and treatment have been impacted globally by the COVID-19 pandemic. In England, prostate cancer accounted for over a third of all missed cancers, and public awareness campaigns to find these ‘missing men’ are ongoing. We aim to identify changes to the characteristics and outcomes of men diagnosed or treated during this period to inform future public health efforts and reduce the impact of COVID-19 on men with prostate cancer.

Methods

A retrospective observational cohort study was conducted using electronic secondary healthcare records from the Hospital Episode Statistics (HES) dataset. The cohort included men aged 45+ with a diagnosis of prostate cancer between 1st October 2018 and 31st March 2021 in England. Sociodemographic characteristics, and treatment and mortality trends of these men were analysed. Characteristics or outcomes pre-COVID-19 and during COVID-19 were compared using the chi squared test.

Results

82,897 men diagnosed pre-pandemic (October 2018-March 2020) and 40,556 diagnosed during the pandemic (April 2020-March 2021) were included in the study. We show a reduction in the proportion of younger men diagnosed with prostate cancer (X²=205.9, df=4, p<0.001). Treatment patterns also shifted. Men with advanced disease accessed novel hormonal therapies as an alternative to chemotherapy during the pandemic. However, more men with advanced disease received no treatment at all. There was an increase in death from any cause in men with prostate cancer (26% during the pandemic compared to 7% prior), which was not accounted for by COVID-19 deaths.

Conclusions

Men who missed a diagnosis of prostate cancer during the pandemic appear to be younger on average than men diagnosed pre-pandemic. Therefore, public health interventions should focus on raising awareness in men under 75. Our overall conclusion from this study is that COVID-19 changed diagnosis and treatment in ways that are likely to increase late diagnosis, increase prostate cancer deaths and reduce life expectancy for men with prostate cancer for many years. This study could help develop public health interventions to help reduce this impact. Currently it applies only to England, but replication in other countries would help to understand the global impact of COVID-19 on men with prostate cancer.

Legal entity responsible for the study

OPEN health/Prostate Cancer UK.

Funding

Prostate Cancer UK.

Disclosure

G. Hall: Financial Interests, Personal, Other, Research as a Subcontractor on Cancer Epidemiology Studies: Gillian Hall. All other authors have declared no conflicts of interest.

Background

In the phase 3 VISION trial, lutetium (¹⁷⁷Lu) vipivotide tetraxetan ([¹⁷⁷Lu]Lu-PSMA-617; ¹⁷⁷Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to protocol-permitted standard of care (SoC) in patients with progressive, PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). The proportion of patients with confirmed decline from baseline in prostate-specific antigen (PSA) level ≥ 50% was higher with ¹⁷⁷Lu-PSMA-617 plus SoC treatment than with SoC alone. This post hoc, exploratory analysis aimed to evaluate associations between magnitude of PSA decline from baseline and clinical outcomes in the ¹⁷⁷Lu-PSMA-617 group.

Methods

Patients in the ¹⁷⁷Lu-PSMA-617 group were classified into four subgroups by magnitude of confirmed best PSA decline from baseline: no decline; ≤ 50% decline; > 50 – ≤ 90% decline; and > 90% decline (cut-off date: 27 January 2021). PSA levels were assessed at baseline and at the start of each six-weekly treatment cycle. Median OS and rPFS were estimated with the Kaplan–Meier method. Hazard ratios (HRs) were estimated using Cox proportional-hazards regression.

Results

Greater PSA decline from baseline was associated with prolonged rPFS and OS in the ¹⁷⁷Lu-PSMA-617 group (Table). Patients with PSA declines > 50 – ≤ 90% and > 90% had an 80% and 96% reduced risk of radiographic disease progression, and a 58% and 90% reduced risk of death, respectively, versus those with no decline. Landmark analyses will also be presented. Table: 1372P

Clinical outcomes by PSA decline subgroups with ¹⁷⁷Lu-PSMA-617

Conclusions

In this analysis, the magnitude of PSA decline from baseline was strongly associated with prolonged rPFS and OS in patients with mCRPC treated with ¹⁷⁷Lu-PSMA-617 plus SoC. This suggests that PSA decline is of prognostic importance for clinical outcomes during radioligand therapy with ¹⁷⁷Lu-PSMA-617 in this patient population.

Clinical trial identification

NCT03511664, 30 April 2018.

Editorial acknowledgement

Under the guidance of the authors, Karim Bensaad, PhD from Oxford PharmaGenesis (Oxford, UK) provided medical writing support for this abstract, with funding from Advanced Accelerator Applications, a Novartis Company.

Legal entity responsible for the study

Advanced Accelerator Applications, a Novartis Company.

Funding

Advanced Accelerator Applications, a Novartis Company.

Disclosure

A.J. Armstrong: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pfizer, AstraZeneca, Forma, Exelixis, Myovant, Dendreon, Clovis, Epic Sciences, Exact Sciences, Janssen, Bayer; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Pfizer, AstraZeneca, Forma, Exelixis, Myovant, Dendreon, Clovis, Genentech/Roche, Amgen, Janssen, Bayer. O. Sartor: Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics, Inc., Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics; Financial Interests, Institutional, Research Grant: Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, MSD, Progenics, Tenebio. F. Saad: Financial Interests, Personal, Advisory Role: Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, Astrazenca; Financial Interests, Institutional, Research Grant: Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, Astraz. J. Czernin: Financial Interests, Personal, Advisory Board, I am was on a medical advisory Board: Amgen; Financial Interests, Personal, Advisory Board, I am a medical advisory board member: Rayze Bio; Financial Interests, Personal, Stocks/Shares, Founder of Sofie Biosciences. I also am a board member: Sofie Biosciences; Financial Interests, Personal, Other, I am a founder. I do not receive any financial compensation: Trethera Corporation. N.D. Shore: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Institutional, Research Grant: Novartis. A.T. Kendi: Financial Interests, Personal, Advisory Board, Prostate, LuPSMA: Novartis; Financial Interests, Institutional, Principal Investigator, VISION study, PI for Mayo Clinic Rochester: Novartis. T.M. Beer: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Constellation, Dantari Pharmaceuticals, GlaxoSmithKline, Grail Inc., Janssen, Myovant Sciences, Novartis, Pfizer, Sanofi, Sapience Therapeutics, Tolero; Financial Interests, Institutional, Research Grant: AllianceFoundation Trials, Astellas Pharma, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Endocyte Inc., Exact Sciences Corp., Freenome, Grail Inc., Harpoon Therapeutics, Janssen, Medivation Inc., MSD, Sotio, Theraclone Sciences/OncoResponse, Zenith Epigenetics; Financial Interests, Personal, Stocks/Shares: Arvinas Inc., Salarius Pharmaceuticals. N. Vaishampayan: Financial Interests, Personal, Advisory Board, Reporting for Spouse: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Reporting for spouse: Exelixis, Pfizer, Bayer, Merck, Aveo, Sonofi; Financial Interests, Personal, Advisory Role, Reporting for spouse: AAA; Financial Interests, Personal, Advisory Board: Novartis. G. El-Haddad: Financial Interests, Personal, Advisory Role: Novartis, Canon Medical, Curium pharma, Boston Scientific, Terumo, Bayer; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. J. Wu: Financial Interests, Personal, Stocks/Shares: Novartis. O. Mirante: Financial Interests, Personal, Stocks/Shares: Novartis. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi, Convergent; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Institutional, Invited Speaker: Novartis, Corcept, Celgen, Janssen.

Background

Multiple targeted therapies have been shown to extend overall survival among men with metastatic castrate resistant prostate cancer including androgen axis modulators, PARP inhibitors, and PSMA theranostics. These and other treatments are being trialed in earlier disease states including in clinically localized prostate cancer. When moved earlier in disease course, therapeutic index and drug effect become more salient. As these therapies are molecularly based, patient subgroups with superior oncological responses might be defined by genomic signatures of their cancer.

Methods

We analyzed the transcriptomes of 52,217 men diagnosed with non-metastatic hormone sensitive prostate cancer for predefined signatures of androgen receptor activity (AR-A), PTEN loss, homologous repair deficiency, RB loss, immune activity, and PSMA expression. We compared signature readouts across NCCN / EAU prostate cancer risk categories.

Results

Median AR-A was highest among men with very low risk prostate cancer and decreased progressively as disease risk/stage increased (P<0.001). Conversely, selected signatures for PTEN loss, homologous recombination deficiency, immune activity, and PSMA expression all increased with disease risk (all P<0.001). PTEN loss rates and rates of homologous recombination deficiency nearly doubled between men suitable for active surveillance and those with unfavorable intermediate disease or greater (7.5% vs 15.3% and 32.2% vs 59.7%, respectively, both P<0.001). While an increase in rates for RB loss was observed among men with very high risk disease at diagnosis, rates remained low at 6.3%.

Conclusions

When considering use of novel targeted therapeutics in localized prostate cancer, agents affecting the androgen axis may be most suited for favorable risk disease while those targeting DNA damage repair deficient tumors, the PI3K/AKT pathway, and PSMA targeted agents are more suitable for exploration in higher risk patients.

Legal entity responsible for the study

Ashley Ross.

Funding

Has not received any funding.

Disclosure

J.A. Proudfoot, A. Hakansson: Financial Interests, Personal, Full or part-time Employment: Veracyte. X. Zhao, Y. Liu, E. Davicioni: Financial Interests, Personal and Institutional, Full or part-time Employment: Veracyte. A. Ross: Financial Interests, Personal, Advisory Role: Veracyte. All other authors have declared no conflicts of interest.

Background

Palliative bone radiation is the predominant skeletal-related event (SRE) reported in prostate cancer. Bone targeted agents (BTA), such as denosumab and zoledronic acid, are shown to prevent and delay SREs. This study evaluated real-world use of BTA in relation to palliative bone radiation prior to prostate-cancer related death using linked provincial databases.

Methods

Linked, administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n=98646), who received continuous androgen deprivation therapy (n=29453), died between 2013-2018 (n=4184), and qualified for Ontario Drug Benefits (≥65 years of age, n=3788). Patients receiving life prolonging therapy (LPT) for metastatic castration-resistant prostate cancer (mCRPC) were selected and use of BTA was identified. Patient characteristics were collected starting 2-years prior to death. Multivariable analyses were conducted to identify factors associated with palliative bone radiation.

Results

1769 patients received LPT for mCRPC, including abiraterone (1094, 62%), docetaxel (881, 60%), enzalutamide (480, 27%), radium-223 (250, 14%) and cabazitaxel (108, 6%). Of these patients, 57% received BTA and 60% received bone radiation. Factors associated with bone radiation were receipt of BTA (95% confidence interval [CI] 1.13-1.91), metastatic disease at diagnosis (CI 1.11-1.97) and radiation oncologist involvement (CI 47.03-226.25), while patients with fewer chronic diseases (CI 0.54-0.98) and who had prior prostatectomy (CI 0.36-0.84) were less likely to undergo bone radiation. The relationship of BTA and bone radiation was maintained for both zoledronic acid (CI 1.09-2.58) and denosumab (CI 1.03-1.77). No specific LPT was associated with use of bone radiation.

Conclusions

Despite clinicians prescribing BTAs to prevent SREs, bone radiation was more likely in patients receiving BTAs. This suggests that clinicians are prescribing BTAs to patients at greater risk of SREs, but patients dying of prostate cancer continue to have significant bone-related morbidity despite contemporary prostate cancer treatment. An analysis of BTA use for primary versus secondary prevention of SREs is being conducted.

Legal entity responsible for the study

The authors.

Funding

Genitourinary medical oncologists of Canada (GUMOC) Astellas Research Grant Program. This work was also supported by ICES (formerly the Institute for Clinical Evaluative Sciences), which is an independent non-profit research institute funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (LMTC).

Disclosure

All authors have declared no conflicts of interest.

Background

Prostate cancer (PCa) is the second most commonly diagnosed neoplasia in men worldwide. The growth of prostate cancer cells is initially dependent of the activity of the androgen receptor (AR) and AR is the target of first-line prostate cancer systemic treatments. The benefit of adding neoadjuvant and adjuvant androgen deprivation therapy is well established for men with high-risk localized and advanced disease. However, some patients develop castration resistant prostate cancer, for which curative options are limited. PTEN is the most often tumor suppressor gene mutated in PCa patients. Hypoxic regions have been found in prostate adenocarcinoma, and elevated expression of hypoxia markers, including HIF1a (hypoxia-inducible factor 1A), have been shown to identify PCa patients with elevated risk of biochemical recurrence.

Methods

Prostate tumors of sham-operated and castrated Pten^(i)pe-/- mice, which have a prostatic luminal cell-specific inactivation of PTEN after puberty, were analyzed by droplet-based single cell-RNA sequencing. Moreover, the impact of genetic and pharmacological Hif1a inhibition was determined in castrated Pten^(i)pe-/- mice by histological analyses.

Results

To gain insights on pathways driving androgen-independence in prostate tumor, we analyzed Pten^(i)pe-/- mice which develop tumors that are resistant to castration. Droplet based single cell-RNA sequencing of 17265 cells from dissociated tumors of castrated and sham-operated Pten^(i)pe-/- mice revealed that androgen deprivation enhances hypoxia signaling in luminal cells. Importantly, this is accompanied by the emergence of an immune-cell-related gene signature in luminal cells of castrated mice, indicating that activation of hypoxic signaling and induction of cellular plasticity are involved in castration resistance. Importantly, genetic ablation of Hif1a in prostatic tumors sensitizes them to castration, and pharmacological inhibition of Hif1a together with androgen deprivation leads to durable anti-tumoral response.

Conclusions

Androgen deprivation in combination with HIF1 signaling inhibition is a promising therapeutic strategy for overcoming castration resistance in PTEN-deficient prostatic tumors.

Legal entity responsible for the study

Daniel Metzger.

Funding

Centre National de la Recherche Scientifique (CNRS) Institut National de la Santé et de la Recherche Médicale (INSERM) Université de Strasbourg Fondation pour la Recherche Médicale grant EQU201903007800 ITMO Cancer within the funds of the Cancer Plan 2014-2019 (administrated by INSERM) and with a collaborative support from the French national cancer Institute Agence Nationale de la Recherche grant ANR-10-LABX-0030-INRT under the frame program Investissements d’Avenir labeled ANR-10-IDEX-0002-02 Fondation ARC pour la Recherche sur le Cancer ITMO Cancer Aviesan / Inserm / Cancer 2020 through the “Formation à la Recherche Fondamentale et Translationnelle en Cancérologie” program.

Disclosure

All authors have declared no conflicts of interest.

Background

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes.

Methods

Patients with advanced prostate cancer who underwent CGP of cfDNA by a CLIA-certified laboratory (Guardant360 testing) between 11/2016 to 8/2020 were eligible. First available cfDNA CGP results from consecutive patients were evaluated for the presence of BRCA1 and/or BRCA2 mutations. All variants of unknown significance were excluded from the analysis. Differences in the genomic landscape of co-segregating genes was investigated by Fisher’s exact test and probabilistic graphical models (PGMs).

Results

In a large dataset of 7,707 men with advanced prostate cancer, 614 men harbored BRCA1 and/or BRCA2 alterations. Results summarized in the table. BRCA1 was significantly associated with 6 other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. Table: 1383P

Conclusions

These hypothesis generating data may explain the increased sensitivity of PARP inhibitors to BRCA2 mutations due to fewer concurrent resistance pathways and guide towards development of combinatorial drug regimens in those with BRCA1 mutation. The limitations of this study include the lack of clinical annotation such as the disease state and treatment exposure.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

U. Swami: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Advisory Board: Seagen, Exelixis; Financial Interests, Institutional, Research Grant: Janssen, Exelixis; Financial Interests, Institutional, Invited Speaker: Astellas/Seattle Genetics. E.J. Hernandez: Financial Interests, Personal, Advisory Role: Fabric Genomics. S. Wesolowski: Financial Interests, Personal, Full or part-time Employment: Recursion Pharmaceuticals. L. Kiedrowski: Financial Interests, Personal, Full or part-time Employment: Guardant Health; Financial Interests, Personal, Stocks/Shares: Guardant Health. P.M. Coelho Barata: Financial Interests, Personal, Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, Clovis Oncology, Dendreon; Financial Interests, Personal, Speaker’s Bureau: Caris Life Sciences, Bayer, Pfizer/Astellas; Financial Interests, Personal, Funding: Blue Earth Diagnostics, AVEO, Pfizer, Merck. G. Lemmon: Financial Interests, Personal, Advisory Role: Backdrop Health. M.A. Bilen: Financial Interests, Personal, Advisory Role: Exelixis, Sanofi, Nektar, EMD Serono, Eisai, Janssen, Genomic Health, Pfizer, BMS, Bayer, Calithera Biosciences, AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Funding: Bayer, BMS, Genentech, Incyte, Nektar, AstraZeneca, Tricon pharmaceuticals, Pfizer, Xencor, Exelixis, Advanced accelerator applications, Genome & Company, Peloton therapeutics, Merck. E. Heath: Financial Interests, Personal, Other, Consulting/Advisory Role, Paid Travel: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb; Financial Interests, Personal, Other, Paid Travel: Caris Life Science; Financial Interests, Personal, Advisory Board, Speaker's Bureau, Paid Travel: Sanofi; Financial Interests, Personal, Advisory Board, Paid Travel: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Celldex, Corcept, Curemeta, Dendreon, eFFECTOR, Esanik, Fortis, Genenctech/Roche, Glaxo Smith Kline, Ignyta, Inovio, Medivation, Merck Sharpe Dohme, Merck, Millenium, Oncolys, Plexxikon, tokai, Zenith; Financial Interests, Personal, Other, Executive Committee Member Precision Oncology Alliance: Caris Life Science; Financial Interests, Personal, Invited Speaker: Seattle Genetics. H. Babiker: Financial Interests, Advisory Role: Endocyte, Celgene, Idera, Myovant Sciences, Novocure; Financial Interests, Speaker’s Bureau: Guardant Health. S.K. Pal: Financial Interests, Personal, Advisory Role: F. Hoffman Laroche, Roche; Financial Interests, Personal, Other, Travel expenses: Genentech, Seattle Genetics; Financial Interests, Institutional, Funding: Eisai, Genentech, Roche, Exelixis, Pfizer. M.B. Lilly: Financial Interests, Personal, Speaker’s Bureau: Guardant Health; Financial Interests, Institutional, Funding: Bavarian Nordic, Bayer. B.L. Maughan: Financial Interests, Personal, Advisory Role: AbbVie, Pfizer, AVEO oncology, Janssen, Astellas, Bristol Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics; Financial Interests, Institutional, Funding: Exelixis (Inst), Bavarian-Nordic (Inst), Clovis (Inst), Genentech (Inst) and Bristol Myers Squibb (Inst). M. Yandell: Financial Interests, Leadership Role: Backdrop Health, IDbyDNA. O. Sartor: Financial Interests, Personal, Advisory Role: AAA, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics,; Financial Interests, Institutional, Research Grant: AAA, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, and Tenebio.; Financial Interests, Personal, Other, travel expemses: Bayer, J&J, Sanofi, AstraZeneca, Progenics; Financial Interests, Personal, Expert Testimony: sanofi; Financial Interests, Personal, Other, patent: Koochekpour, Sartor AO, inventors. Saposin C and receptors as targets for treatment of benign and malignant disorders. US patent awarded January 23, 2007 (patent no. 7,166,691).; Financial Interests, Personal, Stocks/Shares: Lilly, GSK, AbbVie, Cardinal Health, United Health group, PSMA therapeutics, Clarity pharmaceuticals, Noria therapeutics, Clovis Oncology. N. Agarwal: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics.; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis,. All other authors have declared no conflicts of interest.

Background

We have previously shown that radiographic progression-free survival is potentially a valid surrogate of OS. Here, we explore whether castrate-resistant free survival (CRFS) and time to castrate-resistant disease (TCRD) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration.

Methods

We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of CRFS and TCRD as potential ICEs for OS. CRFS was defined as time from randomization to radiographic progression, symptoms, initiation of new treatment, biochemical progression or death from any cause, whichever occurred first; whereas TCRD used the same definition as CRFS except included prostate cancer death only. We implemented a two-stage meta-analytic validation model where conditions of trial-level and patient-level surrogacy had to be met. The surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS.

Results

IPD from 8592 patients randomized from 1994-2012 were analyzed for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 6 years and 4 months. In addition, there were 8260 CRFS and 8215 TCRD events. The median OS, CRFS and TCRD were 49.4, 13.7, and 13.3 months, respectively. The STE was 0.72 for both CRFS and TTCR. Table: 1375P

Conclusions

Both CRFS and TCRD do not appear to be good surrogate endpoints of OS in mHSPC patients.

Clinical trial identification

NCT00002651, NCT00079001, NCT00104715, NCT00268476, NCT00309985, NCT00216060, ISRCTN38477744, NCT00685646.

Legal entity responsible for the study

The authors.

Funding

Prostate Cancer Foundation, UK Prostate Cancer.

Disclosure

S. Halabi: Financial Interests, Personal, Other, Member of DSMB: Sanofi, Aveo Oncology; Financial Interests, Institutional, Funding: ASCO. I.M. Thompson: Financial Interests, Personal, Advisory Board: Profound Medical; Financial Interests, Personal and Institutional, Full or part-time Employment: CHRISTUS Health; Financial Interests, Personal, Member of the Board of Directors: Magenta Health, MagForce USA; Non-Financial Interests, Personal, Advisory Board: National Cancer Institute; Non-Financial Interests, Institutional, Principal Investigator: National Cancer InstituteInstitute. M.A. Carducci: Financial Interests, Personal, Other, Data Safety Monitoring Board: Pfizer; Financial Interests, Personal, Advisory Board: Exelexis; Financial Interests, Personal, Other, JCO Editor: American Society of Clinical Oncology; Financial Interests, Institutional, Invited Speaker: Arcus, Celgene; Non-Financial Interests, Leadership Role: ECOG-ACRIN. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi, Convergent; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Institutional, Invited Speaker: Novartis, Corcept, Celgen, Janssen. G. Gravis Mescam: Financial Interests, Institutional, Advisory Board: AAA, Alliance Merck-Pfizer, Astellas, BMS, Janssen, Pfizer, Ipsen, Alliance Merck-Pfizer; Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Sanofi, Ipsen, AstraZeneca, BMS; Financial Interests, Institutional, Funding: Janssen; Non-Financial Interests, Principal Investigator: Ipsen, BMS, Merck. M.E. Buyse: Financial Interests, Personal, Officer, Chief Scientific Officer: IDDI; Financial Interests, Personal, Invited Speaker, Board Member: CluePoints; Financial Interests, Personal, Stocks/Shares: IDDI, CluePoints. C.J. Sweeney: Financial Interests, Personal, Advisory Board, Consultancy: Genentech, Roche, Bayer, Astellas, Pfizer, Pfizer, Sanofi, Lilly; Financial Interests, Personal, Other, Consultancy: Janssen; Financial Interests, Personal, Stocks/Shares: Leuchemix; Financial Interests, Institutional, Research Grant: Bayer, Janssen, Astellas, Pfizer, Dendreon, Sanofi. All other authors have declared no conflicts of interest.

Background

Landmark trials led to the integration of docetaxel (D) or novel hormonal agents (NHA) added to androgen deprivation therapy (ADT) into the treatment paradigm for mHSPC. Recent data showed survival benefit for treatment intensification with ADT+D+NHA triplet therapy vs ADT+D in selected patients (pts). Yet, there is a significant medical need to expand therapeutic options especially for pts with poor prognoses, including those not candidates for chemotherapy. Abemaciclib is an oral selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 & 6) dosed on a continuous schedule, approved for the treatment of advanced or metastatic and certain types of high-risk early stage HR+, HER2- breast cancer. Analogous to the estrogen receptor signaling pathway in breast cancer, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation, and upregulation of cyclin D1 is a potential mechanism of resistance to NHA therapy. In preclinical models, abemaciclib induces cell cycle arrest and prostate tumor growth inhibition.

Trial design

CYCLONE 3 is a global, randomized, double-blind, placebo-controlled study evaluating the addition of abemaciclib to abiraterone+prednisone (AP) in pts with high-risk mHSPC. Approximately 900 pts with high-risk mHSPC defined by ≥4 bone metastasis and/or visceral disease will be randomised in a 1:1 ratio to the AP + abemaciclib or placebo arm. Up to 3 months of prior ADT alone, or up to 6 cycles of prior D+ADT, is permitted in the absence of radiographic or PSA progression. Pts who have not undergone orchiectomy will continue ADT. Stratification factors are de novo mHSPC, visceral metastases and prior docetaxel use. Primary endpoint is investigator-assessed radiographic progression-free survival (rPFS). Key secondary endpoints include rPFS assessed by blinded independent central review, castration-resistant prostate cancer-free survival, overall survival, time to pain progression, safety and pharmacokinetics. Enrollment is open at approximately 270 sites across 25 countries.

Clinical trial identification

NCT05288166.

Editorial acknowledgement

Scientific writing support was provided by Garreth Lawrence, employee of Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

R.R. McKay: Financial Interests, Personal, Advisory Role: Astellas Medivation, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi, Tempus, Vividion Therapeutics; Financial Interests, Institutional, Funding: Bayer, Pfizer, Tempus. N. Agarwal: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly and Company, EMD Serono, Exelixis, Genentech, Foundation Medicine, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, Seattle Genetics; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, Bavarina Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly and Company, EMD Serono, Exelixis, Genentech, Gilead, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, Tracon. N. Matsubara: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bayer, Chugai Pharma, Janssen, Merck Sharp Dohme; Financial Interests, Personal, Advisory Role: AstraZeneca, Janssen, Eli Lilly and Company, Sanofi; Financial Interests, Institutional, Funding: Astellas Pharma, AstraZeneca, Bayer, Bayer Yakuhin, Chugai Pharma, Janssen, MSD. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati. M.R. Smith: Financial Interests, Personal, Advisory Role: Amgen, Astellas Pharma, Bayer, Janssen Oncology, Eli Lilly and Company, Novartis, Pfizer; Financial Interests, Institutional, Funding: Bayer, Gilead Sciences, Janssen Oncology, Eli Lilly and Company; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Bayer, Janssen, Eli Lilly and Company. T. Todenhöfer: Financial Interests, Personal, Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp Dohme, Roche. T. Zhang: Financial Interests, Personal, Advisory Board: Merck, Exelixis, Sanofi-Aventis, Janssen, AstraZeneca, Pfizer, Amgen, BMS, Pharmacyclics, SeaGen, Calithera, Dendreon, QED Therapeutics, Eisai, Aveo, Bayer, Eli Lilly; Financial Interests, Personal, Other, Consulting: MJH Associates, Vanaiam, Aptitude Health, PeerView, Clinical Care Options; Financial Interests, Institutional, Invited Speaker: Novartis, Merrimack, AbbVie, Merck, Regeneron, Mirati Therapeutics, Janssen, AstraZeneca, Pfizer, Astellas; Financial Interests, Institutional, Research Grant: OmniSeq, PGDx; Non-Financial Interests, Advisory Role, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Advisory Role, Scientific Advisory Board: KCCure; Non-Financial Interests, Advisory Role: Myrovlytis Trust. A.V. Balar: Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company; Financial Interests, Personal, Full or part-time Employment: Loxo Oncology at Eli Lilly and Company. C. Schaverien, S. Sherwood, A. Lithio, K. Nacerddine: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. E. Johnston: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company; Financial Interests, Personal, Other, Travel, Accommodation and Expenses: Eli Lilly and Company. C.J. Sweeney: Financial Interests, Personal, Advisory Role: Sanofi, Janssen, Astellas Pharma, Bayer, Genentech, Pfizer, Eli Lilly and Company, Janssen Biotech, Astellas Pharma, Sanofi; Financial Interests, Institutional, Funding: Bayer, Sotio, Dendreon; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: Patrhenolide (Indiana University), dimethylaminoparthenolide (Leuchemix), Abiraterone plus cabozantinib combination (Exelixis), FRAS1 SNP and tristetraprolin as biomarkers of lethal prostate cancer.

Background

Prospective reports suggest metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. When the addition of androgen-deprivation therapy (ADT) to MDT for omCSPC is needed is unclear. Here we assess the ability of an androgen receptor activity (AR-A) signature to provide prognostic information for omCSPC patients treated with MDT without and with ADT.

Methods

The MDT treatment cohort consisted of patients enrolled on STOMP and ORIOLE trials and similar patients from a retrospective cohort also treated with MDT+/- ADT. RNA next generation sequencing (NGS) was performed on primary prostate tumors from the cohort and AR-A scores were determined. The primary endpoint was time to castration-resistant prostate cancer (ttCRPC). The Kaplan-Meier method and log-rank test were used to assess differences when patients were stratified by median and continuous AR-A score and treatment group. Cox proportional hazard regressions were fit to calculate hazard ratios (HR) and assess the prognostic value of AR-A scores. Our secondary endpoint was proportion of cell types based on PAM50 subtyping.

Results

84 patients were included with median follow-up of 43 months. 5-year ttCRPC was lower with MDT+ADT (3.2%) vs MDT (21.5%) with a pooled HR 0.42 (95% CI, 0.05 – 3.39, p=0.42). Overall, the AR-A was prognostic, in those with high AR-A the 5-year ttCRPC rates were 11.8% vs 33.2% with low AR-A (HR of 0.19, p=0.031). The continuous AR-A scores were also prognostic with HR 0.81 (p=0.023). Patients with high AR-A treated with MDT vs MDT+ADT had similar 5-year ttCRPC (0% vs 11.6%, p=0.289), but there was a significant benefit to the addition of ADT in patients with low AR-A treated with MDT (0% vs 41.9%, p=0.048). PAM50 demonstrated 12% luminal A, 73% luminal B and 15% basal subtypes.

Conclusions

An AR-A signature is prognostic for outcomes in omCSPC treated with MDT and this study suggests that high AR-A patients might derive less benefit from the addition of ADT to MDT. Further validation is needed to optimize omCSPC patient selection for treatment.

Legal entity responsible for the study

Phuoc Tran.

Funding

Anonymous donor, Movember Foundation-Distinguished Gentlemen’s Ride-Prostate Cancer Foundation, Babara's Fund, National Capitol Cancer Research Fund.

Disclosure

P.T. Tran: Financial Interests, Personal, Advisory Board: J&J, RefleXion Medical Inc. A. Hakansson, S. Liu, E. Davicioni: Financial Interests, Personal, Full or part-time Employment: Veracyte. P. Ost: Financial Interests, Personal, Research Grant: Bayer. All other authors have declared no conflicts of interest.

Background

In the phase 3 ARCHES trial, >90% of men with mHSPC received prior ADT and achieved a range of PSA values (≤0.2, >0.2−4, and >4 μg/L) before randomization. This post hoc analysis examined the effect of treatment intensification with ENZA + ADT versus continuing ADT alone on OS and other efficacy outcomes by baseline PSA categories.

Methods

Pts with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT. Prior ADT (≤3 months [mo]/≤6 mo + docetaxel) and up to 6 cycles of prior docetaxel were permitted before baseline assessment of PSA levels and study treatment initiation. After unblinding, 31.3% of PBO + ADT-treated pts crossed over to open-label ENZA + ADT (median time to crossover, 21.5 mo). Post hoc analyses of the primary endpoint radiographic progression-free survival (rPFS) and secondary endpoints such as OS were conducted to assess the efficacy of ENZA + ADT in pts achieving different baseline PSA categories after prior treatment with ADT.

Results

In the overall population (n=1150), >90% received prior ADT and 18% had prior docetaxel treatment. Median duration (range) of prior ADT was 1.6 mo (0.03–55.3) for ENZA + ADT pts versus 1.6 mo (0.03–198.8) for PBO + ADT pts. Of the overall population with available baseline PSA values who received prior ADT (n=1045), 133 pts had ≤0.2 μg/L, 372 had >0.2−4 μg/L, and 540 had >4 μg/L PSA at baseline (Table). A beneficial effect of ENZA + ADT was observed across all baseline PSA categories, including OS (adjusted for crossover) in pts with baseline PSA ≤0.2 μg/L, with no evidence of heterogeneity (Table).

Conclusions

These post hoc analyses in pts with mHSPC who received prior ADT and achieved baseline PSA values even to ≤0.2 μg/L support the additional durable clinical benefits of treatment intensification with ENZA + ADT for rPFS and OS and other secondary endpoints. Table: 1398P

Clinical trial identification

NCT02677896.

Editorial acknowledgement

Medical writing and editorial assistance were provided by Laura Gibbons, PhD, Lauren Smith, BA (Hons), and Jane Beck, MA, from Complete HealthVizion, funded by the study sponsors.

Legal entity responsible for the study

Astellas Pharma Inc.; Pfizer Inc.

Funding

This study was funded by Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide.

Disclosure

D.P. Petrylak: Financial Interests, Institutional, Research Grant: Ada Cap (Advanced Accelerator Applications), Agensys Inc., Astellas Pharma Inc., AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Lilly, Endocyte, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, Seattle Genetics; Financial Interests, Personal, Other, Consultant fees: Astellas Pharma Inc., Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Exelixis, Johnson&Johnson/Janssen, Lilly, Clovis Oncology, Roche, Seattle Genetics, Ada Cap (Advanced Accelerator Applications), Amgen, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Incyte, Mirati, Monopteros, Pharmacyclics, Gilead Sciences, Ipsen, Regeneron, UroGen; Financial Interests, Personal, Expert Testimony: Sanofi, Celgene; Financial Interests, Personal, Stocks/Shares, sold 10/2019: Tyme; Financial Interests, Personal, Stocks/Shares, sold 7/2020: Bellicum Pharmaceuticals. A.A. Azad: Financial Interests, Personal, Research Grant: Astellas, AstraZeneca, Merck-Serono, Bayer; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb, AstraZeneca, Aptevo Therapeutics, Glaxo Smith Kline, MedImmune, Astellas, SYNthorx, Bionomics, Sanofi Aventis, Novartis, Ipsen, Exelixis, Merck Sharpe Dome, Janssen; Financial Interests, Personal, Advisory Role: Astellas, Novartis, Pfizer, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Bayer, Telix Pharmaceuticals, MSD, Aculeus Therapeutics, Amgen, Merck Serono, Ipsen, Noxopharm; Financial Interests, Personal, Speaker’s Bureau: Astellas, Janssen, Ipsen, Bristol Myers Squibb, Merck Serono, Novartis, Amgen, Bayer; Financial Interests, Personal, Other, Travel/accommodations/expenses: Astellas, Pfizer, Novartis, Janssen, Tolmar, Amgen, Merck-Serono; Financial Interests, Personal, Advisory Board: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, MSD, Amgen, Noxopharm; Financial Interests, Personal, Other, Data Safety Monitoring Board: Oncosec; Non-Financial Interests, Personal, Leadership Role: ANZUP Cancer Trials Group, COSA. R.Z. Szmulewitz: Financial Interests, Personal, Advisory Role: AstraZeneca, AbbVie, Exelixis, Merck, Amgen, Sanofi, Astellas Pharma Inc., Pfizer, Janssen Oncology; Financial Interests, Personal, Other, Honoraria: Astellas Pharma Inc.; Financial Interests, Personal, Other, Travel/Accommodations/Expences: Corcept Therapeutics; Financial Interests, Institutional, Other, Patent Co Inventor: Corcept Therapeutics; Financial Interests, Personal and Institutional, Funding: AbbVie, Astellas Pharma Inc., Incyte, Macrogenics, Janssen Oncology. T. Iguchi: Financial Interests, Personal, Advisory Role: Astellas Pharma Inc., Bayer, Janssen; Financial Interests, Personal, Speaker’s Bureau: Astellas Pharma Inc., Bayer, Janssen, Sanofi, AstraZeneca, Takeda; Financial Interests, Institutional, Funding: Astellas Pharma Inc., Bayer. N.D. Shore: Financial Interests, Personal, Advisory Role: Bayer, Janssen Scientific Affairs, Dendreon, Tolmar, Ferring, Medivation, Amgen, Pfizer, AstraZeneca, Genentech/Roche, Myovant Sciences, Astellas Pharma; Financial Interests, Personal, Speaker’s Bureau: Janssen, Bayer, Dendreon. J. Holzbeierlein: Financial Interests, Institutional, Funding: Astellas Pharma Inc.; Financial Interests, Institutional, Principal Investigator: MDxHealth. B. Alekseev: Financial Interests, Personal, Advisory Role: Astellas Pharma Inc., Pfizer, AstraZeneca, Bayer, BMS, Ferring, Janssen, MSD, Sanofi, Eisai, Roche; Financial Interests, Personal, Speaker’s Bureau: Astellas Pharma Inc., Pfizer, AstraZeneca, Bayer, BMS, Ferring, Janssen, MSD, Sanofi, Eisai; Financial Interests, Personal, Other, Travel/accommodation/expenses: Astellas Pharma Inc., Pfizer, AstraZeneca, Bayer, BMS, Ferring, Janssen, MSD, Sanofi, Eisai; Financial Interests, Institutional, Funding: Astellas Pharma Inc., Pfizer, AstraZeneca, Bayer, BMS, Janssen, MSD. N.N. El-Chaar: Financial Interests, Personal, Other, Travel, accomodations, expenses: Astellas Pharma Inc.; Financial Interests, Personal, Stocks/Shares: TNXP, SNGX, BNGO, SESN, RXRX; Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Inc. B. Rosbrook: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. J. Ma: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Inc. F. Zohren: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: AlloVir, Inc., Pfizer. G.P. Haas: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Inc. A. Stenzl: Financial Interests, Personal, Advisory Role: Astellas Pharma Inc., Ipsen Pharma, Roche, Janssen, Ferring, Synergo, Molecular Health, miRScientific, AstraZeneca; Financial Interests, Personal, Invited Speaker: Ipsen Pharma, Astellas Pharma Inc., Janssen, Ferring, AstraZeneca; Financial Interests, Personal, Expert Testimony, photodynamic therapy of prostrate cancer: GBA; Financial Interests, Personal, Other, Travel/accommodations/expenses: Ipsen Pharma, Janssen, Ferring, CureVac, Sanofi Aventis; Financial Interests, Personal, Other, Patents (A290/99, AT00/0001:C-Trap, 2018/6579): N/A; Financial Interests, Personal, Principal Investigator: Astellas Pharma Inc., Medivation, Roche, Janssen, Karl Storz AG, AstraZeneca, Johnson&Johnson, Cepheid, Amgen, CureVac, Immatics, GemeDX Bioscience, Novartis. A.J. Armstrong: Financial Interests, Personal, Advisory Role: Astellas Pharma Inc., Pfizer, Medivation, Bayer, Forma, Novartis, Dendreon, Janssen, Merck, AstraZeneca, BMS, Exelixis, Epic Sciences, Myovant; Financial Interests, Personal, Other, Travel/accommodations/expenses: Astellas Pharma Inc.; Financial Interests, Institutional, Funding: Astellas Pharma Inc., Pfizer, Medivation, Bayer, Forma, Novartis, Dendreon, Janssen, Merck, AstraZeneca, Roche/Genentech, Bristol Myers Squibb, Amgen.

Background

Preliminary results of the SPLASH (NCT04647526) lead-in, a phase 3 study evaluating the PSMA targeted radioligand, ¹⁷⁷Lu-PNT2002 (also known as ¹⁷⁷Lu-PSMA I&T), in PSMA-positive patients with mCRPC who progressed after treatment with androgen receptor axis-targeted therapy (ARAT), are herein presented.

Methods

This multi-national, open-label study commenced with a 27-patient lead-in prior to the randomization. Patients were enrolled with tumors exhibiting high-PSMA uptake on positron emission tomography–computed tomography (PSMA PET/CT) per blinded independent central review (BICR), chemotherapy naïve for CRPC, progressing on an ARAT, and adequate bone marrow and end organ reserve. Patients received up to four cycles of ¹⁷⁷Lu-PNT2002 at 6.8 GBq per cycle every 8 weeks and were followed for key endpoints of radiographic progression-free survival (rPFS) per BICR, overall survival, PSA response, dosimetry and safety.

Results

33 men underwent PSMA PET/CT to identify 27 (81.8%) eligible for treatment, of which 5 (15.2%) failed due to PSMA avidity criteria. Patients received a median 4 cycles of ¹⁷⁷Lu-PNT2002, with a median dose of 6.9 (6.2-7.5) GBq/cycle. Six (22%) patients who underwent treatment received a prior taxane for hormone-sensitive disease. Based on a median rPFS follow-up of 7.5 months at data cut-off, 21 (78%) remained event-free with a rPFS rate at 9 months of 75.4%. There was one death reported (non-treatment related) and 11 (42%) patients achieved a PSA50 response. Grade ≥3 treatment emergent adverse events (TEAEs) occurred in 8 (29.6%) patients, of which anaemia (3, 11.1%) and haematuria (3,11.1%) occurred in >10% of patients. Treatment-related TEAEs in > 10% patients included dry mouth (7, 25.9%), nausea (5, 18.5%), fatigue (5, 18.5%), haematuria and anaemia (3, 11.1%).

Conclusions

In mCRPC patients post-ARAT failure, ¹⁷⁷Lu-PNT2002 was associated with a favorable rPFS and was well-tolerated. Anti-neoplastic efficacy was exhibited based on PSA50 response. These results support the advancement of ¹⁷⁷Lu-PNT2002 to the randomized portion of the SPLASH registrational trial.

Clinical trial identification

NCT04647526.

Editorial acknowledgement

None

Legal entity responsible for the study

POINT Biopharma.

Funding

POINT Biopharma.

Disclosure

A.R. Hansen, R.F. Tutrone, M.M. Osman, E.S. Delpassand, L.T. Nordquist, B.L. Viglianti, J.M. Michalski, J. Beauregard, O.K. Oz, K. Courtney: Non-Financial Interests, Institutional, Principal Investigator: POINT Biopharma. S. Probst: Financial Interests, Personal, Invited Speaker: POINT Biopharma; Non-Financial Interests, Institutional, Principal Investigator: POINT Biopharma; Non-Financial Interests, Personal, Advisory Role: POINT Biopharma. J. Jensen: Financial Interests, Personal, Full or part-time Employment: POINT Biopharma; Financial Interests, Personal, Stocks/Shares: POINT Biopharma; Non-Financial Interests, Personal, Officer: POINT Biopharma; Non-Financial Interests, Personal, Proprietary Information: POINT Biopharma; Non-Financial Interests, Personal, Sponsor/Funding: POINT Biopharma; Non-Financial Interests, Personal, Leadership Role: POINT Biopharma. W. Wu: Financial Interests, Personal, Full or part-time Employment: POINT Biopharma; Financial Interests, Personal, Stocks/Shares: POINT Biopharma; Non-Financial Interests, Personal, Sponsor/Funding: POINT Biopharma. N. Fleshner: Financial Interests, Personal, Officer: POINT Biopharma; Financial Interests, Personal, Full or part-time Employment: POINT Biopharma; Financial Interests, Personal, Ownership Interest: POINT Biopharma; Financial Interests, Personal, Stocks/Shares: POINT Biopharma; Non-Financial Interests, Personal, Proprietary Information: POINT Biopharma; Non-Financial Interests, Personal, Sponsor/Funding: POINT Biopharma; Non-Financial Interests, Personal, Advisory Role: POINT Biopharma; Non-Financial Interests, Personal, Leadership Role: POINT Biopharma. O. Sartor: Non-Financial Interests, Institutional, Principal Investigator: POINT Biopharma; Financial Interests, Personal, Advisory Board: POINT Biopharma; Financial Interests, Personal, Stocks/Shares: POINT Biopharma; Financial Interests, Personal, Advisory Role: POINT Biopharma. K.N. Chi: Non-Financial Interests, Institutional, Principal Investigator: POINT Biopharma; Financial Interests, Personal, Advisory Role: POINT Biopharma; Financial Interests, Personal, Advisory Board: POINT Biopharma. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: EMD Serono, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Invited Speaker: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen, Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Phosplatin.

Background

Resistance to ARSIs (e.g. abiraterone, enzalutamide) is inevitable and there is critical need to develop new therapies for mCRPC. SG is an antibody-drug conjugate targeting Trop-2, currently FDA-approved for use in breast and bladder cancers.

Methods

An open label, phase II trial of SG for pts with mCRPC progressing on ARSIs, stratified by prior chemo vs. chemo naïve, was opened to evaluate the efficacy of SG. Pts were required to have rising PSA and radiographic progression on ARSI in the mCRPC setting. The two primary endpoints were 6-month radiographic progression-free survival (rPFS) and PSA50 response. A separate analysis of Trop-2 expression in prostate cancer biopsies and association with genomic markers of ARSI resistance were also analyzed in 4 previously curated cohorts (n = 632) and the PROMOTE study (n = 88).

Results

Twenty pts were enrolled in this Phase II trial at the time of interim analysis. Pts had a median PSA of 47.2ng/mL at baseline. All pts had metastatic disease, with 90% bone only metastases. All pts had progressed on an ARSI with 30% of pts having received docetaxel chemotherapy in the castration sensitive setting. Neutropenia was the most common adverse event (AE) across all grades, observed in 85% of pts though easily managed with GCSF and only 1 episode of febrile neutropenia. Nausea, diarrhea, anemia, and alopecia were observed in ≥50% of pts, with only four grade 3 AEs. The 6-month rPFS rate was 45% in all pts and 64% of chemo-naïve pts, with the longest treated pt on trial for 62 weeks. No PSA50 responses were observed although PSA stabilization occurred in all pts that met the 6-month rPFS endpoint. We also report that Trop-2 is expressed in >80% of pts with mCRPC and associated with luminal and basal subtypes, suggesting Trop-2 as a high value therapeutic target in mCRPC.

Conclusions

SG has clinical activity in mCRPC progressing on prior ARSI(s) based on 6-month rPFS, which warrants further clinical investigation. PSA stabilization was observed in pts meeting this endpoint. Analysis of tissue and liquid biopsies is ongoing to identify predictive biomarkers for SG in prostate cancer.

Clinical trial identification

NCT03725761.

Legal entity responsible for the study

Carbone Cancer Center, University of Wisconsin-Madison.

Funding

Gilead, Prostate Cancer Foundation.

Disclosure

J. Lang: Financial Interests, Personal, Advisory Board: Pfizer, Janssen, Gilead, 4D Pharma, Arvinas, Astellas, Myovant, AstraZeneca, Seagen; Financial Interests, Institutional, Invited Speaker: Gilead, Pfizer, Arvinas, Seagen. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: EMD Serono, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Invited Speaker: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen, Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Phosplatin. S. Slovin: Financial Interests, Personal, Invited Speaker, Speaker: Physician Education Resource; Financial Interests, Personal, Other, Grant Reviewer: NCI; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Clovis, LabCorp. H. Emamekhoo: Financial Interests, Personal, Advisory Board: Exelixis, Seattle Genetics. D. Rathkopf: Financial Interests, Invited Speaker: Janssen, Janssen, Genentech; Financial Interests, Research Grant: Genentech; Non-Financial Interests, Advisory Role: Janssen, Genentech, AstraZeneca, Myovant; Non-Financial Interests, Principal Investigator: Janssen, Genentech, Phosplatin, Taiho, Celgene/BMS; Non-Financial Interests, Other, Drug supplied by Bayer for Investigator-led trial: Bayer. W. Abida: Financial Interests, Personal, Invited Speaker: Roche, Medscape, Aptitude Health, Onclive, Clinical Education Alliance, TouchIME; Financial Interests, Personal, Advisory Board: Clovis Oncology, Janssen, ORIC Pharmaceuticals, Daiichi, AstraZeneca UK; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Zenith Epigenetics, Clovis Oncology, ORIC Pharmaceuticals, Epizyme; Non-Financial Interests, Member: ASCO. K. Autio: Financial Interests, Institutional, Invited Speaker, Funding to institution for trial conduct: Amgen, Lilly, Parker Institute for Cancer Immunotherapy, AstraZeneca, Trishula, GSK; Financial Interests, Institutional, Invited Speaker, Lead PI - Funding to institution for trial conduct: Pfizer. A.M. Molina: Financial Interests, Personal, Advisory Board: Janssen, Eisa, Exelixis. J. Eickhoff: Financial Interests, Personal, Other, Consultant: AbbVie. S. Dehm: Financial Interests, Personal, Other, Scientific Consultant: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Oncternal Therapeutics. D.M. Nanus: Financial Interests, Personal, Invited Speaker, Participated in roundtable: AstraZeneca; Financial Interests, Institutional, Invited Speaker, PI Clinical Trial: Exelixis; Financial Interests, Institutional, Invited Speaker, Site Lead Clinical Trial: Zenith Epigenetics. C.E. Kyriakopoulos: Financial Interests, Personal, Advisory Board: Exelixis, AVEO, Sanofi-Aventis, EMD Serono, Janssen Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Gilead, Incyte Corporation, Sanofi-Aventis, AstraZeneca. All other authors have declared no conflicts of interest.