1. Abstract Number - 5083

Title: Bayer is gearing up to unveil a post hoc analysis from the Phase III ARASENS trial in patients with mHSPC, further underpinning the potent efficacy profile of darolutamide. 

Commentary - Bayer is all set to present the post hoc analysis from the Phase III ARASENS trial.

Executive Summary – NUBEQA (darolutamide) has been approved for use in combination with docetaxel for patients with mHSPC, based on the results of the double-blind ARASENS trial. Bayer is set to present findings on post-progression subsequent anticancer therapies and related survival outcomes from the ARASENS trial.

Main Content – 

In August 2022, the US FDA approved NUBEQA (darolutamide) tablets in combination with docetaxel for adult patients with metastatic hormone-sensitive prostate cancer (mHSPC) based on results from the Phase III ARASENS trial (NCT02799602). Prior to this, it had been approved for treating patients with non-metastatic castration-resistant prostate cancer (nmCRPC) based on the results of the Phase III ARAMIS trial (NCT02200614).

At the upcoming ASCO conference, a poster session will present new data on NUBEQA, including a post hoc analysis from the Phase III ARASENS trial. This analysis evaluates post-progression survival with darolutamide and androgen deprivation therapy (ADT) plus docetaxel in patients with mHSPC.

Bayer has emphasized that NUBEQA is the only androgen receptor inhibitor (ARi) approved in combination with docetaxel for mHSPC. NUBEQA has quickly gained traction and maintained strong growth across all regions, particularly in the United States, Europe, and China. Bayer is also strategizing to expand NUBEQA's prescription volume by targeting patients ineligible for chemotherapy through the ARANOTE Phase III trial. The company is on track to treat 70,000 patients and surpass USD 1 billion in total sales this year.

Conclusion: NUBEQA (darolutamide) data will include a post hoc analysis from the Phase III ARASENS trial, evaluating post-progression survival with darolutamide and ADT plus docetaxel in patients with mHSPC. This analysis will further underscore the potent efficacy profile of darolutamide.

2. Abstract Number – 5001

Title: Lilly’s CDK4/6 inhibitor, VERZENIO fails to meet the primary endpoint of improved radiographic progression-free survival in mCRPC patients. 

Commentary - In an oral presentation, Eli Lilly will report the primary results of CYCLONE 2, a Phase III study of ABEMA plus abiraterone (ABI) in patients with 1L mCRPC at the upcoming ASCO meeting. 

Executive Summary – Eli Lilly will be presenting primary results from CYCLONE 2, a Phase III study of ABEMA plus abiraterone (ABI) in patients with 1L mCRPC at the upcoming ASCO meeting. News of its flop came in February. 

Main Content –  In recent months, Eli Lilly has faced two consecutive trial failures for VERZENIO in prostate cancer. In February, news broke about the CYCLONE-2 trial failure. During its Q4 2023 earnings call, Eli Lilly reported that VERZENIO combined with abiraterone did not meet the primary endpoint of improved radiographic progression-free survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the Phase III CYCLONE-2 study. Furthermore, in its Q1 2024 earnings call, Eli Lilly announced the termination of the Phase III CYCLONE-3 trial evaluating VERZENIO in metastatic hormone-sensitive prostate cancer (mHSPC) due to futility following an interim analysis.

Following these setbacks, Eli Lilly is now focusing on PNT2002, a PSMA-targeted radioligand therapy and potential competitor to Novartis’ PLUVICTO. In October 2023, Eli Lilly acquired POINT, with PNT2002 being POINT's lead asset.

Conclusion: Eli Lilly will be discussing the negative findings from CYCLONE 2, a Phase III study of ABEMA plus abiraterone (ABI) in patients with 1L mCRPC at the upcoming ASCO meeting.

3. Abstract Number – 5061

Title: Pfizer is all set to highlight longer-term follow-up from the dose escalation cohort of Mevrometostat (PF-06821497) in combination with XTANDI in CRPC.

Commentary - At ASCO 2024, Pfizer will be presenting a poster session highlighting the Phase I trial of mevrometostat (PF-06821497), a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in CRPC.

Executive Summary – At ASCO 2024, Pfizer will be showcasing a poster session detailing the Phase I trial of mevrometostat (PF-06821497), a highly potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), for the treatment of castration-resistant prostate cancer (CRPC).

Main Content – At the European Society of Medical Oncology (ESMO) Congress 2022, Pfizer shared the results of their EZH2 inhibitor, mevrometostat (PF-06821497), primarily focused on determining the optimal dose and maximizing tolerability. This year, Pfizer is prepared to present updated Phase I data on mevrometostat in combination with XTANDI for metastatic castration-resistant prostate cancer (mCRPC) at the ASCO 2024 meeting. The company also plans to initiate Phase III studies for this combination later this year. Initially, PF-06821497 targeted follicular lymphoma, castration-resistant prostate cancer (CRPC), and small-cell lung cancer. The trial was divided into two parts: the first tested PF-06821497 alone, administered twice daily in escalating doses across all three diseases, while the second evaluated PF-06821497 in combination therapy specifically for prostate cancer.

Conclusion: The ESMO data in 2022 represented Pfizer's initial foray into this emerging class of therapies, which appears to be gaining momentum. In 2020, the FDA granted accelerated approval to Epizyme’s tazemetostat, the first-in-class inhibitor of the epigenetic writer EZH2, for the treatment of epithelioid sarcoma. Several other EZH2 inhibitors are currently under investigation for various indications, including Morphosys’ tulmimetostat and Jiangsu Hengrui Medicine’s SHR2554. Observing the performance of Pfizer’s EZH2 inhibitor, mevrometostat at the upcoming conference will be intriguing.

Abstract Number – 5060

Title: Results from the first-in-human Phase I STESIDES study evaluating ODM-209, a CYP11A1 inhibitor in patients with mCRPC to be showcased at ASCO 2024. 

Commentary – Merck and Orion to present findings from the STESIDES Phase I trial on ODM-209, a CYP 11A1 inhibitor in mCRPC, at the ASCO 2024. 

Executive Summary – ODM-209 is a novel, oral selective inhibitor of CYP11A1, that blocks the production of all steroid hormones and precursors that may activate hormone receptor signaling pathways. Orion will be discussing results from the first-in-man Phase I STESIDES study (NCT03878823) at the upcoming conference. 

Main Content – ODM-209 is a novel, oral selective inhibitor of CYP11A1, which blocks the production of all steroid hormones and their precursors that could activate hormone receptor signaling pathways, such as androgen or estrogen. Its mode of action is similar to that of ODM-208/MK-5684, which is currently in Phase III clinical development for metastatic castration-resistant prostate cancer (mCRPC). 

In their 2021 financial statement release, Orion reported that by the end of the review period, the company decided to focus on ODM-208 over ODM-209, choosing between the two novel selective hormone synthesis inhibitors (CYP11A1 inhibitors). 

In July 2022, Merck announced a global development and commercialization agreement for Orion’s investigational candidate ODM-208 and other drugs targeting cytochrome P450 11A1 (CYP11A1), an enzyme crucial in steroid production.

Conclusion: According to Orion’s full-year 2021 results presentation, the development of ODM-209 was terminated in favor of advancing ODM-208. It will be interesting to see if ODM-209 might be revisited for the treatment of prostate cancer in the future. Currently, ODM-209 is not listed in Orion’s pipeline.

Abstract Number – 5012

Title: Amgen is set to unveil initial data from the DeLLpro-300 study exploring the potential of tarlatamab in treating de novo or treatment-emergent neuroendocrine prostate cancer. 

Commentary – Following its recent FDA approval for extensive-stage small cell lung cancer, Amgen is poised to present initial data on IMDELLTRA (tarlatamab) for treating de novo or treatment-emergent neuroendocrine prostate cancer patients.

Executive Summary –  Amgen will be presenting initial data from the DeLLpro-300 Phase Ib study at the ASCO 2024 meeting. This study evaluates IMDELLTRA (tarlatamab), a bispecific T-cell engager immunotherapy that binds DLL3 and CD3, leading to T-cell mediated tumor lysis, for the treatment of de novo or treatment-emergent neuroendocrine prostate cancer.

Main Content –  IMDELLTRA (tarlatamab) is a first-in-class immunotherapy engineered by Amgen researchers that binds to both DLL3 on tumor cells and CD3 on T cells, activating T cells to kill DLL3-expressing cells. DLL3 is overexpressed in high-grade neuroendocrine carcinoma, including NEPC, and minimally expressed on normal tissue. 

Amgen's robust tarlatamab development program includes the DeLLphi clinical trials, which evaluate tarlatamab as both a monotherapy and in combination regimens in earlier lines of SCLC, and DeLLpro clinical trials, which evaluate the efficacy and safety of tarlatamab in neuroendocrine prostate cancer. Tarlatamab joins Xaluritamig another BiTE molecule looking at tackling prostate cancer. The US FDA in May 2024 approved IMDELLTRA as the first and only T-cell engager therapy for the treatment of extensive-stage small-cell lung cancer. 

Conclusion: Neuroendocrine prostate cancer is an aggressive form of prostate cancer characterized by a poor prognosis and a lack of standard treatment options. It will be intriguing to see how tarlatamab has performed in this challenging segment.

Abstract Number – 5010

Title: J&J reveals mixed results for next-generation radiopharmaceutical JNJ-6420, highlighting four patient deaths in an early-stage prostate cancer trial. 

Commentary – Ahead of ASCO annual meeting, Johnson & Johnson reported that four patients died during the Phase I study of its investigational targeted radiopharmaceutical candidate JNJ-6420 for mCRPC.

Executive Summary –  Profound and durable biochemical and radiographic responses were seen in patients treated with one to two doses of 150-μCi JNJ-6420. However, as of the January 5 2024 data cutoff, four patients died in the Phase I study. 

Main Content –  JNJ-6420 is an antibody-based targeted radioligand therapy that uses an anti-hK2 antibody to deliver a high-energy, short-range alpha-particle emitter specifically to prostate cancer cells. This therapy was evaluated in its first human study, which involved patients with metastatic castration-resistant prostate cancer who had received at least one prior treatment with an androgen receptor pathway inhibitor. The readout released on Thursday noted that as of January 5, 2024, JNJ-6420 spurred one complete response, two partial responses, and three confirmed objective responses. Grade ≥3 TEAEs (≥10%) included anemia (26.3%), thrombocytopenia (17.5%), lymphopenia (10.5%), and leukopenia (10.5%). 9/57 (15.8%) patients discontinued treatment due to TRAEs; 4 TRAEs resulted in death.

Major pharmaceutical companies have increasingly focused on radiopharmaceuticals, with Novartis being successful in the field due to its two approved drugs, PLUVICTO and LUTATHERA. It will be intriguing to observe the performance of Johnson & Johnson's radiopharmaceutical, JNJ-6420, in prostate cancer, especially considering its mixed results thus far.

Conclusion: The results released on ASCO’s website so far indicate that one to two doses of 150-μCi JNJ-6420 can elicit profound and durable biochemical and radiographic responses in treated patients. However, regarding safety, J&J’s investigational radiotherapy appears to be quite toxic.

Abstract Number – 5011

Title: Arvinas is all set to report initial results from a Phase I/II study (NCT05067140) of ARV-766 in men with mCRPC and disease progression on prior NHA therapy. 

Commentary – Arvinas will be presenting initial results from a Phase I/II study in mCRPC evaluating its second-generation PAN AR-targeting PROTAC degrader, ARV-766 at the upcoming ASCO conference. 

Executive Summary –  With anticipated pending regulatory discussions in 2Q24 for the initiation of a pivotal Phase III trial of ARV-766 in post-NHA (mCRPC), Arvinas is all geared up to report initial results from a Phase I/II study (NCT05067140) of ARV-766 in men with mCRPC and disease progression on prior NHA therapy at the conference. 

Main Content –  ARV-766 is an investigational, orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR).  The company’s last update came in ESMO 2023 with a data cut-off date of August 23, 2023. A PSA50 of 41% in patients with tumors harboring any AR LBD mutation, and a PSA50 of 50% in patients with any tumor harboring an AR L702H mutation were reported. ARV-766 was well-tolerated, with no grade ≥ 4 TRAEs. The most common TRAEs were grade 1 or 2 and included fatigue (29%), nausea (14%), vomiting (11%), and diarrhea (11%). The discontinuation rate due to TRAEs was 4%. 

ARV-766 was out-licensed to Novartis in April 2024, with a pivotal Phase III trial anticipated pending regulatory discussions in the second quarter of 2024. 

Conclusion: Arvinas has recognized the importance of targeting mutant degradation to address drug resistance that can develop in patients using AR inhibitors like Astellas and Pfizer's XTANDI, as well as Johnson & Johnson's ZYTIGA. Additionally, Arvinas sees opportunities for ARV-766, its PROTAC AR degrader, in earlier lines of therapy. It will be intriguing to see if the potential of ARV-766 is reinforced by the initial results of the Phase I/II study (NCT05067140) in men with mCRPC and disease progression on prior NHA therapy.