Month: September 2019

The U.S. Food and Drug Administration (FDA) has approved Erleada (apalutamide) for the treatment of men with metastatic, castration (hormone)-sensitive prostate cancer (mCSPC), or those whose cancer still responds to androgen deprivation (hormonal) therapy (ADT).

The decision is based on the double-blind TITAN Phase 3 trial (NCT02489318), as it showed that adding Janssen’s Erleada to ADT significantly extended both overall survival and progression-free survival (PFS) – the period without cancer progression –, which were the trial’s primary goals. Based on results from the SPARTAN clinical trial, Erleada had already been approved in 2018 as a treatment for patients with non-metastatic (localized) castration (hormone)-resistant prostate cancer in both the United States and the European Union.

Compared to ADT and a placebo, treatment with Erleada and ADT reduced the risk of death by 33%, and the likelihood of disease worsening (as assessed by radiography) or death by 52%. After a median follow-up of 22.7 months, 84% of the patients on Erleada and ADT reached the two-year mark alive, compared to 78% of those on ADT and placebo. In this indication, Earleada decreased the risk of cancer spreading or death by 72 percent compared to a placebo, and delayed the cancer’s metastasis by more than two years. The frequency of serious adverse events was 19.8% for Erleada and 20.3% for placebo.

Erleada is an oral therapy that targets the androgen receptor, blocking its activation by androgens such as testosterone. Its chemical structure and mode of action are similar to that of enzalutamide (Xtandi). In turn, ADT, a mainstay of prostate cancer treatment, reduces the amount of androgens in the body.

TITAN included 1,052 mCSPC patients regardless of extent of disease and of being newly diagnosed or having been treated with up to six cycles of docetaxel (taxotere). It was funded by Johnson & Johnson-owned Aragon Pharmaceuticals and Janssen Research and Development (also owned by Johnson & Johnson). The study’s findings were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine.

“Prostate cancer is more difficult to treat once it spreads, and for patients with castration (hormone)-sensitive disease, it is clear that androgen deprivation therapy (ADT) alone is often not enough,” Kim Chi, principal investigator in TITAN and medical oncologist at BC Cancer-Vancouver, said in a press release. “Results from the TITAN study showed that, regardless of the extent of disease, patients with metastatic castration-sensitive prostate cancer have the potential to benefit from treatment with Erleada in addition to ADT.”

Most information in this post appeared in the September 19th, 2019 Prostate Cancer News Today by Jose Marques Lopes, Ph.D.

Tumors with large numbers of prostate cancer cells with mutations in DNA repair genes (e.g. BRCA1 and 2) are easier to target using prostate-specific membrane antigen (PSMA) therapies, and patients with these tumors are more likely to respond to this potential treatment’s use, a study found and published in European Urology.

PSMA is a membrane protein often found at very high levels on the surface of prostate cancer cells, especially among those forming castration (hormone)-resistant prostate cancer (CRPC) tumors, an aggressive form of the disease that no longer responds to hormone therapy.

For that reason, PSMA has become a promising target of researchers working to develop a new class of medications that combine an anti-PSMA antibody with a radioactive moiety. Such medications, like lutetium (Lu)177-PSMA, use the anti-PSMA antibody to specifically spot and deliver the radioactive lutetium-177 conjugate to prostate cancer cells which produce PSMA in large amounts.

But this type of targeted radiation therapy does not work for all patients, and the rates of those failing to respond have amounted to about 30% in studies. Between 30% to 60% of patients with metastatic CRPC (mCRPC) treated with these therapies, however, have reported reductions of more than 50% in PSA levels (a biomarker of prostate cancer).

Prior studies used antibodies that target the intracellular (not the surface) part of PSMA, which has no clinical value for estimating PSMA levels. A team of investigators at the Institute of Cancer Research in London set out to characterize the levels of PSMA found specifically on the surface of prostate cancer cells — called membranous PSMA (mPMSA) — in a group of men with mCRPC. Because mutations in DNA repair genes lead to a high genetic variability within a single tumor, researchers also examined if these mutations affect PSMA levels and could be used to guide PSMA-directed therapies.

The study involved two groups of patients: a test group of 60 patients who provided mCRPC tissue samples, including 38 people with matched, castration (hormone)-sensitive prostate cancer (CSPC) diagnostic samples; and a confirmation group of 10 patients whose tumors contained a high number of mutations in DNA repair genes.

Despite the high degree of variability in membranous PSMA levels evident among different patients and even between samples obtained from the same patient, high levels of mPSMA at diagnosis generally associated with greater cancer aggressiveness (based on the Gleason score) and poorer patient survival.

In addition, researchers found that membranous PSMA (mPSMA) levels tended to be higher in metastatic hormone-resistant prostate cancer samples compared to hormone-sensitive samples, or samples from patients whose tumors respond to hormone therapies.

Investigators also found that mPSMA levels were more than four times higher in tumors containing numerous mutations in DNA repair genes, compared to those with no mutations. These findings were confirmed in the second group of study patients.

Testing for DNA repair defects was a good indication of which tumors had high levels of PSMA — and so would be expected to respond to these PSMA-targeted therapies like lutetium-177-PSMA. Identifying patients with DNA repair mutations could be useful in design of clinical trials to identify likely responders to PSMA treatments. (I was recently informed that genetic testing for DNA repair mutations is commercially available from the company Invitae.)

For additional details see the Aug. 22 Prostate Cancer News Today.