10 cancer symptoms men shouldn't ignore

Bayer Completes US Filing For Prostate Cancer Drug Darolutamide

Bayer has completed its rolling marketing application for prostate cancer drug darolutamide in the US, setting up possible approval later this year and a market clash with Pfizer/Astellas and Johnson & Johnson.

The filing is based on data from the phase III ARAMIS trial of Orion-partnered darolutamide plus androgen deprivation therapy (ADT) in patients with non-metastatic castration-resistant prostate cancer (CRPC). The results were published in the New England Journal of Medicine earlier this month and showed the drug extended metastasis-free survival (MFS) compared to placebo plus ADT.

Darolutamide is being cued up as a rival to J&J's already-marketed androgen receptor antagonist Erleada (apalutamide) as well as Pfizer/Astellas' Xtandi (enzalutamide), which are already approved for non-metastatic CRPC and so will be the primary, direct competitors for darolutamide if it reaches the market.

Bayer and Orion think their drug could however offer a safety advantage, and has the potential to become a 1 billion-euro-plus product if approved. Analysts at Jefferies have said however that while the side effect profile was favourable, that may not be enough to take on its established rivals because their efficacy data is comparable.

Darolutamide has been fast-tracked by the FDA for non-metastatic CRPC, which is associated with a high risk for cancer progression and mortality, so a verdict could be speedy. Meanwhile, the two partners are in discussion about filing the drug with other world regulators, including in Europe.

Under the terms of Bayer and Orion's 2014 deal, the latter is eligible to receive payments of 45 million euros, 20 million euros and 8 million euros upon the first commercial sale in the US, EU and Japan, respectively.

In ARAMIS, the median MFS was 40.4 months in the darolutamide arm compared to 18.4 months in the placebo arm, which is equivalent to a 59% reduction in the risk of metastases or death. There was a trend towards an increase in overall survival of 29% versus placebo.

Bayer and Orion say darolutamide has a benign safety profile, which they suggest stems from a novel structure meaning that – unlike Xtandi and Erleada – it is unable to cross the blood-brain barrier. The two marketed drugs are associated with increased cognitive impairments, falls, and other side effects.

J&J's older androgen receptor antagonist Zytiga (abiraterone) is another big product in the prostate cancer category but is currently only approved to treat tumours that have already metastasised to other parts of the body.

Non-metastatic CRPC is still an emerging area of the prostate cancer therapeutic category, given that both Xtandi and Erleada were only approved for this indication in the US in the last few months.

Analysts reckon that it could however become a multibillion-dollar market, as long as the MFS data that supported approval is followed by improvements in overall survival that could be needed to help encourage payer reimbursement.

Orion and Bayer also have an ongoing phase 3 clinical trial – called ARASENS – which is evaluating darolutamide in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and is expected to read out in 2022.

Pfizer and Astellas recently reported positive results from the ARCHES trial of Xtandi in this patient population.

Analyzing AE Data To Guide Selection Of Androgen Receptor Inhibitors In MHSPC

Targeted Therapies in Oncology: What are the goals of therapy for this patient with newly diagnosed mHSPC?

A: EVAN Y. YU, MD: When I see a patient like this, what I do first is consider the patient's prognosis. I also need to consider whether this person is presenting with de novo metastatic prostate cancer, or [whether] they have recurrent disease—for example, [whether] they had initially been treated for prostate cancer with either radical prostatectomy or radiation, and now, years later, the disease has recurred. The patients who recur years later have a much better prognosis.

Then I evaluate the volume of disease, which is shown through either visceral lesions or bone metastases. This patient has 4 bony lesions with at least 1 outside of the axial skeleton.

Then I have a conversation with the patient about their prognosis, and how aggressive I believe the disease is. The key goal is to prolong survival for as long as possible. I realize this may be an incurable disease state; however, I also know that we have many good treatment options for our patients. Thus, extending overall survival [OS] is our No. 1 goal.

A close-second goal is quality of life. Thus, it is not just about extending survival, but about extending survival with outstanding quality of life. We have to be mindful to balance our aggressiveness in relation to treatment with the potential adverse events [AEs] of that treatment.

What systemic therapy options would you discuss with a patient?

A: My default approach for frontline treatment is a doublet therapy, which includes ADT with a luteinizing hormone–releasing hormone [LHRH] agonist or antagonist, such as leuprolide [Lupron], along with the addition of an androgen receptor pathway inhibitor.

The FDA-approved agents that show OS benefit include abiraterone [Zytiga], enzalutamide [Xtandi], and apalutamide [Erleada]. We recently received data from the ARANOTE trial [NCT04736199] that [were] presented at the 2024 European Society for Medical Oncology [ESMO] Congress.1

The data regarding darolutamide [Nubeqa] plus ADT look favorable. We are waiting to see whether there will be regulatory approval for darolutamide as a doublet with LHRH therapy soon in the US.

The other consideration is when to do triplet therapy. We could consider triplet therapy with the addition of docetaxel [Taxotere] to the regimen. This depends on the patient's prognostic characteristics such as high or low volume of disease and [whether] they present with de novo or recurrent disease.

In general, I find that the patient population that presents with de novo and has high-volume disease is similar to those from the ARASENS trial [NCT02799602] and would benefit with ADT, darolutamide, and docetaxel.2

The triplet therapy of ADT, abiraterone, and docetaxel shows good quality level 1 data for these patients [PEACE-1 trial; NCT01957436].3 Both of those regimens may benefit a patient with de novo, high-volume disease.

Now, there may be other populations that could benefit with docetaxel, but this requires a discussion about how fit the patient is, their comorbidities, and [whether] they are an ideal candidate to receive docetaxel and tolerate any potential AEs.

I would probably lean toward recommending triplet therapy for this patient who has de novo, high-volume disease.

However, if this patient strongly prefers to avoid chemotherapy, and given that they only slightly meet the criteria for high-volume disease, we would then have an in-depth discussion about which androgen receptor pathway inhibitor would be the most appropriate treatment.

Evan Y. Yu, MD

Professor

Division of Hematology and Oncology

University of Washington

Professor

Clinical Research Division

Fred Hutchinson Cancer Center

Medical Director

Clinical Research Support

Fred Hutchinson Cancer Consortium

Clinical Research Director

Genitourinary Oncology

University of Washington

Seattle, WA

How do you choose which androgen receptor pathway inhibitor to administer?

A: I tend to prefer both abiraterone and darolutamide because of the associated AEs. Enzalutamide and apalutamide cause more fatigue issues. I like to use abiraterone as my first-line agent. Darolutamide also demonstrated improved efficacy in randomized, controlled trials and did not increase fatigue.2

In addition, abiraterone and darolutamide are the 2 androgen receptor pathway inhibitors that pair well with docetaxel as shown by the PEACE-1 trial evaluating triplet therapy.3 Thus, for those reasons I lean toward these agents.

That said, I have no problem with the use of enzalutamide or apalutamide. They just do not have the level 1 evidence to support triplet therapy with docetaxel.

What other factors should be considered for patients with mHSPC?

If you are considering which doublet androgen receptor pathway inhibitor combination to use and you have a patient with brittle diabetes you have to use low-dose prednisone with abiraterone. This consideration may sway you from using abiraterone. Likewise, if you have a patient with liver issues, abiraterone can cause transaminitis. In addition, if a patient has heart failure issues, abiraterone can cause mineralocorticoid excess. For these patients, abiraterone may not be an ideal treatment.

However, for patients who are more advanced in age, have dementia issues, or [have] cognitive dysfunction, these patients may be more susceptible to the brain fog and fatigue that enzalutamide causes. Apalutamide tends to cause rash AEs, and for a patient with skin issues I would lean away from using apalutamide.

There are also drug-interaction issues, such as issues with CYP3A4 inhibition or enhancement issues, and darolutamide does tend to have less drug-to-drug interactions than some of the other androgen receptor pathway inhibitors. Thus, these are some of the issues that I consider when choosing which agents I would use. As mentioned, I have a preference toward either abiraterone and darolutamide, because they cause less fatigue, and that tends to be a deciding factor. However, as discussed, there are other subtle comorbidities and AEs that one should consider when deciding between the different antigen receptor pathway inhibitors.

This patient wants to avoid chemotherapy; how would you proceed?

I would counsel the patient on the fact that this [method] is different. This is single-agent docetaxel. It is similar to chemotherapy vs other drug regimens we use for other cancers. Ultimately, we must respect the patient's wishes. I would counsel him on the risks and benefits of the treatment options, and if he chooses to avoid chemotherapy, we would proceed with a doublet therapy and discuss ADT with an androgen receptor pathway inhibitor.

Can you explain some of the new data from ESMO?

The newest data presented at ESMO 2024 were [from] the ARANOTE study, which was conducted outside the US.1 This was a randomized phase 3 trial for patients with mHSPC who were receiving initial treatment. Patients were randomly assigned 2:1 to ADT plus darolutamide 600 mg twice daily vs placebo plus ADT. The trial included about 670 patients, and the primary end point was radiographic PFS.

There are some interesting baseline characteristics to point out in this trial: Almost one-third of the patients were from Asia. In the study, there was a high population of patients from Asia, and there was around 10% of patients who were Black. Thus, this study had a more diverse makeup of patients compared with some of the other trials that exist. Otherwise, the [patient] characteristics are very similar to those in the [phase 3] ARCHES trial [NCT02677896].4

In the ARCHES trial, patients with mHSPC were randomly assigned to ADT plus enzalutamide. Almost [three-fourths] of the patients had de novo metastatic disease upon presentation, and about 70% of the patients had high-volume disease. Thus, the ARANOTE trial matches fairly well, in terms of demographics, with the other studies.1

In the ARANOTE trial, the end point of radiographic PFS was very positive with an HR of 0.54, which is statistically significant in favor of ADT and darolutamide vs placebo and ADT. Although the OS data are not yet mature, this looks very similar to what we saw in the ARCHES study at this phase in the trial.4 Investigators first presented the radiographic PFS data and subsequently later, when there were enough events, the OS data were also very significant. Thus, I would anticipate no difference with the ARANOTE study.1 I believe that in the near future we will see positive OS data that look very similar to what we saw in the ARCHES trial.4

What about the safety data available for these regimens?

One aspect that is nice to consider with darolutamide is that, as shown by the ARANOTE trial, there are minimal [associated] AEs.1 When evaluating the data, the number of serious AEs was 23% in both arms, with darolutamide and with placebo. However, when you look at the most common treatment-emergent AEs, what you find is most interesting. In almost every study in oncology, you typically see more fatigue with the study drug than with the control arm. But in this situation the incidence of fatigue was 5.6% for darolutamide and 8.1% for the placebo arm. Thus, there was more fatigue in the placebo arm.

Regarding mental impairment disorder, because androgen receptor inhibitors do cross the blood-brain barrier, although darolutamide may cross the barrier less because it has a different biochemical structure, you still see a little bit of increase. It is 1.6% with darolutamide vs 0.5% for placebo.

Other AEs that you might see with other agents, such as an increase in fall risk with enzalutamide, we did not see in this study. The fall risk was 1.3% with darolutamide vs 0.9% with placebo. We did also see an increase in bone fractures, but it was very slight: 4% for darolutamide and 2.3% for placebo. In general, [this regimen is] very safe and demonstrates quite an impressive AE profile.

Collectively, how are you applying trial results to treatment decision-making?

When I consider all the data with the androgen receptor pathway inhibitors, the key aspect I am focused on is the AEs, and the reason I am focused on that is because I do not believe one is better than another in terms of efficacy. We cannot know for sure, because we do not have direct comparisons between enzalutamide, apalutamide, darolutamide, and abiraterone. However, we do see significant survival benefit with all these drugs in different combinations of studies. We can, however, compare the difference between the treatment arm and the control arm in each of these studies, and I believe that there are wider gaps with agents like enzalutamide between the treatment arm and the control arm in terms of AEs.

For instance, abiraterone does not elicit much fatigue. When you observe the data for darolutamide, you see numerically, maybe not statistically, but numerically less fatigue.

Thus, these are the factors that I am considering as I observe the data: I am evaluating the AEs between the treatment arm and the control arm, and how much difference there is between the critical AEs, such as fatigue, cognitive AEs, and fall risk, which I f ind to be most critical. These are critical for our patient population, especially an aging patient population.

In addition, now that we have triplet therapies that are generally used for patients who have de novo, high-volume disease, I consider this when choosing the androgen receptor pathway inhibitor.

As mentioned, only 2 agents have triplet combination phase 3 studies that have been performed and that are positive. These are ADT plus abiraterone and docetaxel from the PEACE-1 trial and ADT plus darolutamide with docetaxel in the ARASENS trial. Thus, these are other factors I also consider.2,3

Would you consider adding chemotherapy to a doublet regimen on an as-needed basis?

This is a practical question in the case of this patient, who chose to receive an androgen receptor pathway inhibitor doublet and not a triplet with chemotherapy: Would I add chemotherapy later?

With most of these studies there is a 3-month window to add an additional androgen receptor pathway inhibitor or additional chemotherapy. This is an important option to consider, and I believe in the [phase 3] CHAARTED trial [NCT00309985], there was a 4-month window with docetaxel.5

However, most of the trials give a 3-month window, and this is because a patient may just receive a Lupron [injection] and then see an oncologist later. Then we would consider treatment intensification with androgen receptor pathway inhibitor or docetaxel chemotherapy.

Therefore, it is normal to add those therapies later, and the label for darolutamide with docetaxel, for instance, says that you can start with darolutamide and then add the chemotherapy later. I believe it specifies a 12-week window or so.

That is one typical approach that is helpful, because sometimes it is beneficial to f irst see how well the patient tolerates the doublet therapy and then decide whether to add the chemotherapy later.

Now, there is a bigger-picture question: Are there patient populations where we start with a doublet, and we realize that the patient has worse risk than we thought?

There are a couple studies that are being planned right now through cooperative groups.

These include the National Clinical Trials Network and Alliance for Clinical Trials in Oncology, that are planning to focus on tumor suppressor genes to help identify populations with differing prognostic outcomes, such as PTEN, TP53, and Rb mutations.

Those with PTEN mutation may not have as poor a prognosis, but TP53 is considered a worse prognostic indicator, and Rb represents the most significant negative prognostic factor. Thus, these patients may need chemotherapy more so, and if you were to do next-generation sequencing and find these prognostic factors, should you then add the chemotherapy? This is the unanswered question, but Alliance for Clinical Trials in Oncology is going to ask that question and [SWOG] and the Canadian Cancer Trials Group are going to ask this in addition to evaluating PSA. For example, what if you treat patients with a doublet ADT and an androgen receptor pathway inhibitor, and then after about 6 months or so the PSA becomes undetectable? If the PSA becomes undetectable, we know that this a good prognostic patient population, and perhaps we do not need more treatment intensification.

However, if the PSA does not become undetectable, those patients will be [randomly assigned] to continue receiving a doublet vs adding in chemotherapy. These are some of the next steps taking place in the future that will ask real, practical questions that I believe the field needs answers on.

REFERENCES 1. Saad F, Egils Vjaters, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):42714281. Doi.10.1200/jco-24-01798 2. Hussain M, Bertrand Tombal, Saad F, et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol. 2023;41(20):3595-3607. Doi.10.1200/jco.23.00041 3. Bossi A, Foulon S, Maldonado X, et al. Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): Results of PEACE-1, a phase 3 randomized trial with a 2x2 design. J Clin Oncol. 2023;41(suppl 17):LBA5000. Doi.10.1200/jco.2023.41.17_suppl. Lba5000 4. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. Doi.10.1200/jco.19.00799 5. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):10801087. Doi:10.1200/JCO.2017.75.3657

Bayer Triples Sales Forecast For Prostate Cancer Drug Nubeqa

Bayer now says it expects to make €3 billion in sales for its prostate cancer treatment Nubeqa, up from an earlier estimate of €1 billion, after reviewing new data for the drug in metastatic hormone-sensitive tumours.

The optimistic assessment of the revenue potential for androgen receptor inhibitor Nubeqa (darolutamide) follows the publication of the results of the phase 3 ARASENS trial in the New England Journal of Medicine.

The study showed that adding Nubeqa to standard therapy with anti-androgen drugs and chemotherapy with docetaxel reduced the risk of dying by 32.5% compared to standard therapy alone. There was also a big increase in the duration of response, from a media of just under 17 months to 41 months.

The data will be filed with regulatory authorities to seek an expansion of the label for Nubeqa, according to Bayer, which developed Nubeqa in collaboration with Finland's Orion.

The drug is already approved to treat non-metastatic castration-resistant prostate cancer (CRPC), but expansion into hormone-sensitive prostate cancer could unlock a sizeable new market for the drug.

That would allow Nubeqa to try to claim market share from other more established drugs in the oral androgen receptor inhibitor class, including Johnson & Johnson's Erleada (apalutamide) and Pfizer/Astellas' Xtandi (enzalutamide), although analysts have suggested that could be a tough proposition as physicians have more experience with the current drugs.

The hike in projected revenues comes from "confirmation of darolutamide's clinical profile and expansion into the metastatic setting as well as the investments that we are making in clinical trials in other potential indications," said Bayer's pharma chief Stefan Oelrich.

That includes a second phase 3 trial in metastatic hormone-sensitive prostate cancer, ARANOTE, and the ANZUP trial looking at adjuvant (post-surgery) use of Nubeqa in localised prostate cancer with a high risk of recurrence.

Bayer hasn't published its fourth-quarter results yet, but said in its third-quarter announcement that it was expecting sales of Nubeqa in non-metastatic CRPC to reach between €200 million and €250 million in 2021.

If Bayer's optimistic predictions are proved correct it will be a major boost to the company, which is facing the threat of competition to big-selling pharma products Eylea (aflibercept) for ophthalmic diseases and anticoagulant Xarelto (rivaroxaban) in the coming years.

Nubeqa is one of three drugs that the company is hoping will help it weather that impact on revenues, along with recently-approved diabetic kidney disease therapy Kerendia (finerenone) and elinzanetant for menopausal symptoms.

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