2:14 PM
Mar 01, 2019
 |  BioCentury  |  Product Development

Prostate cancer disrupted

Why the treatment paradigm for prostate cancer could soon see a shake-up

Two imminent disruptions threaten to upend the treatment landscape for prostate cancer, changing who gets anti-androgen therapies and ushering in the first new MOAs in decades.

The launch of generic abiraterone means next generation anti-androgens in development will likely be pushed into earlier settings than the late-stage disease Johnson & Johnson’s branded Zytiga abiraterone has traditionally treated.

On the other hand, new mechanisms are entering the scene. And given the resistance likely to develop to the anti-androgens, the new MOA compounds may be able to step straight into a treatment void in late disease settings.

Reduced androgen signaling has been the major goal of prostate cancer treatment for over sixty years, first via surgical or chemical castration, then through targeted therapies. The reason is that almost all prostate cancers are heavily dependent on androgen receptor activation and only become independent late in disease, after anti-androgen therapy.

But where modern anti-androgens slot into the treatment paradigm could rapidly change due to the launch of generic forms of Zytiga, which has been one of the most successful next-generation prostate cancer drugs. Its 2018 sales were $3.5 billion.

Zytiga and its closest competitor Xtandi enzalutamide from Pfizer Inc. and Astellas Pharma Inc. were initially approved in metastatic castration-resistant prostate cancer (mCRPC). However, data presented over the past several years -- most recently at the American Society of Clinical Oncology 2019 Genitourinary Cancers Symposium (ASCO GU) -- have demonstrated that the anti-androgen class is equally effective in two earlier disease settings, non-metastatic CRPC and metastatic hormone-sensitive prostate cancer (mHSPC) (see Figure: “Treatment Continuum”).

According to three physicians who spoke to BioCentury, the efficacy of anti-androgens and the lack of differentiation between them means generic abiraterone may eventually dominate in these earlier prostate cancer settings.

“I’m thinking that the generic abiraterone, if it gets cheap enough, is really a disrupter,” A. Oliver Sartor, professor of medicine at Tulane University and medical director of Tulane Cancer Center, told BioCentury.

“Generic abiraterone, if it gets cheap enough, is really a disrupter.”

A. Oliver Sartor, Tulane University

The best bet for companies with next-generation androgen therapies may be to push earlier still, into settings such as localized prostate cancer where there aren’t clinical data supporting a benefit for Zytiga.

Whether doctors prescribe the generic drug in those settings may boil down to their individual comfort levels with relying on data from other anti-androgens.

In all events, as anti-androgens march up the treatment paradigm, they threaten to leave a void in mCRPC, because clinical data do not support using multiple anti-androgens in succession, due to cross-resistance.

“What you are doing is supplanting the androgen axis as a viable target in metastatic CRPC because all of these agents are moving up front,” said Sartor.

The gap may be filled by new MOAs that are coming down the pike due to a better understanding of the genetic makeup of prostate cancer. The most promising of these new MOAs, the doctors agreed, are molecules against prostate-specific membrane antigen (PSMA; FOLH1; GCPII) and PARP. 

Figure: Treatment continuum

After initial approvals in metastatic castration-resistant disease, anti-androgen therapies are moving up the treatment paradigm in prostate cancer.

Localized prostate cancer: Early stage localized prostate cancer is usually treated with watchful waiting or more aggressive active surveillance of PSA levels via frequent biopsies. As PSA levels increase, patients may receive radiotherapy, prostatectomy or androgen-deprivation therapy (ADT). With the Phase III ATLAS and PROTEUS trials of Erleada apalutamide, Johnson & Johnson (NYSE:JNJ) is the first company to test an androgen receptor inhibitor in this setting.

Non-metastatic hormone-sensitive prostate cancer (HSPC): Patients with non-metastatic HSPC may also receive ADT or radiotherapy. Both Erleada and androgen receptor inhibitor Xtandi enzalutamide from Pfizer Inc. (NYSE:PFE) and Astellas Pharma Inc. (Tokyo:4502) are in Phase III trials in the setting. The first data from the EMBARK study of Xtandi are expected in 2020.The NCT03777982 trial has not yet started.

Metastatic hormone-sensitive prostate cancer (mHSPC): J&J’s anti-androgen therapy Zytiga abiraterone is approved to treat mHSPC, and Xtandi and Erleada...

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