Today (19 November) marks International Men’s Day with the theme for 2024 being Men’s Health Champions, shining a light on the problems of men’s health and the people at the heart of delivering the solution.
Prostate cancer is the most common cancer among men and the second leading cause of cancer death for men in the United States. There are a range of treatment options for men diagnosed with prostate cancer, but as many are diagnosed late due to symptoms taking time to develop, there is a need for more therapies for later-stage patients, especially for patients where certain therapies have failed.
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In the UK, the number of men getting tested for prostate cancer has increased dramatically after Olympian Sir Chris Hoy announced he had been diagnosed with terminal prostate cancer.
There are several candidates under investigation for prostate cancer for patients at various stages of the disease including an oncolytic virus, PARP inhibitor and EZH2 inhibitor.
Candel Therapeutics trialling oncolytic virus therapy combo
Candel Therapeutics is running a Phase III PrTK03 trial (NCT01436968) evaluating the effectiveness of its CAN-2409 (aglatimagene besadenovec) immunotherapy in combination with radiation therapy for patients with intermediate-high risk localised prostate cancer. The trial is due to complete in December 2024.
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By GlobalDataThe placebo-controlled study is estimated to enrol 711 patients in the US and Puerto Rico who have been monitored every six months for five years. The primary endpoint is disease-free survival. Patients in the treatment arm have received CAN-2409, valacyclovir, radiation therapy and potentially short-term androgen deprivation therapy (ADT). Meanwhile, the placebo group received placebo, valacyclovir, radiation therapy and potentially short-term ADT.
CAN-2409 uses an inactivated herpetic virus to directly deliver a gene to cancer cells, followed by an anti-herpetic therapy with Valtrex (valacyclovir), killing the cells containing the gene.
Dr. Robert Dreicer, deputy director of the University of Virginia Cancer Center, said that allowing the investigator to give hormonal therapy could be a cofounder in the trial, but still does not have high hopes.
“It's certainly a rational study and I think it would be extremely provocative if it turned out to be a positive study,” Dreicer said. “The only therapeutic vaccine that's approved is Provenge (sipuleucel-T) which is a completely different mechanism so we don't know whether this particular oncolytic viral approach will have clinical activity yet,” Dreicer concluded.
Dr. Daniel Petrylak, chief of Genitourinary Oncology at Yale University, said this is an interesting trial to watch considering previous immune checkpoint failures.
“Generally immune checkpoint therapy has not worked in patients with prostate cancer,” said Petrylak. “There is the abscopal effect which shows a potential synergy between radiation therapy and immune therapy. This states you can augment the immune response by combining immune therapy with radiation therapy. But are we going to see that here?”
Johnson & Johnson’s Akeega being investigated in early stage
Johnson & Johnson’s AMPLITUDE study (NCT04497844) is evaluating Akeega, a dual action tablet combining niraparib, a PARP inhibitor, with abiraterone acetate, given with prednisone, versus abiraterone acetate and prednisone for the treatment of participants with deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-sensitive prostate cancer (mCSPC). The primary completion date is November 2024.
The trial has enrolled 696 patients across 387 sites globally. The primary endpoint is radiographic progression-free survival (rPFS). In the treatment arm, patients will receive Akeega. Meanwhile, in the active comparator arm, patients will receive abiraterone acetate plus prednisone.
In the Phase III MAGNITUDE trial, BRCA-positive patients treated with the combination Akeega plus prednisone saw a statistically significant 47% risk reduction observed for rPFS. Patients without BRCA mutations did not show as strong a benefit in the study.
The combination therapy approval from the US Food and Drug Administration (FDA) for the treatment of adult patients with deleterious or suspected deleterious BRCA-positive metastatic castration-resistant prostate cancer (mCRPC), as detected by an FDA-approved test.
Dreicer said that Johnson & Johnson’s study is also a rational approach but states that the data from MAGNITUDE suggests there may be more benefit in patients who had a mutation in either of the BRCA1 and BRCA2 genes.
“The utility may also be seen in the other DDR mutations, but likely to be less impactful,” Drecier explains. “The industry at large thinks this is a very important kind of trial because identifying BRCA patients or other DDR mutations who have more aggressive disease biology and bringing a targeted therapy like a PARP inhibitor will hopefully move the needle.”
Petrylak is more hopeful for this study but has concerns about a potential increase in toxicity, such as myelodysplastic syndrome (MDS) or secondary or leukaemia, by giving these drugs earlier. As a result, long-term analysis will be very important.
“This is a very interesting study. In patients with DDR mutations, there is synergy in the castration-resistant state between PARP inhibitors and next-generation antiandrogens. This trial moves this up earlier in the course of disease and potentially you may see more of an effect. I'm eagerly anticipating the results of this trial because we may see something quite robust with this,” Petrylak explains.
Biswajit Podder, PhD, oncology, and haematology analyst for GlobalData believes that should the trial be efficacious, this could become the standard of care for this patient population.
“Should the trial yield positive results, this combination could be the standard-of-care for the patients with deleterious germline or somatic HRR Gene-Mutated mHSPC. However, given the limited size of the target population, the impact on the broader prostate cancer treatment market may be small,” Podder says.
Pfizer investigational candidate inhibits EZH2
Pfizer is running a Phase III trial (NCT06551324) which is investigating its investigational candidate mevrometostat (PF-06821497) in men with mCRPC who were previously treated with abiraterone acetate. The trial has a primary completion in December 2025.
The MEVPRO-1 study is estimated to enrol 600 patients across 25 sites in the US, Australia, and Asia. The primary endpoint is rPFS for up to two years. The treatment arm will receive mevrometostat twice daily plus enzalutamide daily. Meanwhile, the active comparator arm will receive a physician’s choice of enzalutamide or docetaxel.
Mevrometostat blocks the effects of a protein called enhancer of zeste homolog 2 (EZH2). EZH2 is involved in prostate cancer cell growth. One of the targets involved in this process is a protein called H3K27Me3, which decreases cancer cell growth.
“This trial is important because it's testing a novel pathway that's not really been fully explored. One of the major challenges in managing prostate cancer is what to do in patients who progressed on androgen receptor pathway inhibitors. The androgen receptor remains the holy grail in treating prostate cancer, and there have been innumerable efforts using a variety of classes of agents to try to overcome some of this resistance. EZH2 when mutated, can act as a co-activator for the androgen receptor so targeting that pathway is another way to try to overcome AR pathway resistance.”
Dreicer says an important part of this study is the ability to choose enzalutamide or docetaxel, with the latter being considered a more modern control.
“This particular drug inhibits EZH2 which may be one of the resistance pathways to androgens. The problem with a trial like this is you are only going to see a real signal in Phase III so it’s very difficult to say at this stage whether this will work,” Petrylak concludes.
Podder has concerns with the trial, mostly with the trial design and lack of single-agent investigative arm.
“A key limitation of this trial is the choice of comparator arm, as it does not include a single-agent mevrometostat arm,” Podder states.
“Additionally, the trial design raises concerns by reintroducing an androgen therapy to patients who have already shown progression on similar therapy, which may not be an ideal control approach. Patients are unlikely to respond effectively to another anti-androgen therapy after failing a similar treatment, and chemotherapy is increasingly being incorporated at earlier stages in the treatment paradigm. If the trial demonstrates positive outcomes, Mevrometostat could become the first EZH2 inhibitor for prostate cancer, although competition in this space is expected to be small.”
Update: This article has been updated to change the name of Candel Therapeutics's candidate.
