At the 2019 American Society of Clinical Oncology (ACSO) Annual Meeting, results presented by two PCF-funded investigators from pivotal phase 3 clinical trials will likely lead to approval of a new class of life-extending treatment options for men with metastatic hormone-sensitive prostate cancer (mHSPC).
mHSPC refers to men whose prostate cancer has spread to areas of the body outside of the prostate itself, and who are responsive to testosterone-lowering agents. This may refer to men who have had prior surgery or radiation and recurred, or men who were initially diagnosed with disease that was already metastatic (outside the prostate). Patients who are “hormone-sensitive” (aka, “castration-sensitive”) may have previously received androgen deprivation therapy (ADT) for a certain amount of time, but their cancer has not yet developed resistance to ADT.
Until 2015, the standard-of-care treatment for men with mHSPC was ADT alone. ADT is a class of treatments that block the production or activity of testosterone, which fuels the growth of prostate cancer cells.
In 2015, the phase III CHAARTED trial demonstrated that if men with a high volume of mHSPC were given docetaxel chemotherapy in addition to ADT, they would live an average of 17 months longer than with ADT alone. In 2017, results from the phase III LATITUDE and STAMPEDE trials demonstrated that if men with high volume or high risk mHSPC received abiraterone in addition to ADT, they would also live longer: about 17 months longer on average in LATITUDE. Patients who have a lower burden of metastatic disease do better on ADT alone, and only the addition of abiraterone had been shown to improve their survival. Docetaxel is a chemotherapy, whereas abiraterone is a hormonal therapy which decreases testosterone-like hormones outside of the testicles.
Now, results from new trials will likely add two more drugs to the treatment arsenal for mHSPC. Both of these drugs are potent direct inhibitors of the androgen receptor (AR).
At ASCO 2019, results were presented from the randomized, double-blinded phase III TITAN trial by PCF-funded investigator Dr. Kim Chi, MD, of the Vancouver Prostate Centre. The TITAN trial tested the addition of apalutamide (Erleada) versus placebo, to ADT in 1,052 men with mHSPC. Patients on this trial had could have previously received ADT for no more than 6 months for mHSPC or no more than 3 years if used as adjuvant therapy for localized prostate cancer, and were not on ADT at the time of disease progression and trial enrollment. Patients could also have previously received docetaxel chemotherapy for no more than 6 cycles, and could not have progressed on that treatment.
Compared with a placebo, the addition of apalutamide to ADT significantly reduced the risk of death by 33%, and reduced the risk of radiographic disease progression (tumors growing on scans) or death (whichever came first) by 52%. Apalutamide also significantly delayed the average time to PSA progression, use of chemotherapy, and pain progression. Apalutamide was shown to prolong survival of patients with both low and high volume metastatic disease. The treatment combination was considered tolerable, and quality of life in patients receiving apalutamide was similar to those receiving placebo in addition to ADT. Adverse effects that were higher in patients receiving apalutamide vs placebo included rash (27% vs. 8.5% of patients), hypothyroidism (6.5% vs. 1.1% of patients), and fractures (6.3% vs. 4.6% of patients).
Results from a second randomized phase III trial, ENZAMET, an academic study led by a new cooperative group called ANZUP in collaboration with Canadian Cancer Trials Group, Cancer Trials Ireland and Dana-Farber Cancer Institute, were also presented at ASCO by PCF-funded investigator Dr. Christopher Sweeney, MBBS (Harvard: Dana Farber Cancer Institute). ENZAMET tested the addition of enzalutamide (Xtandi) versus a standard-of-care nonsteroidal anti-androgen therapy (bicalutamide, nilutamide, or flutamide) to ADT in 1,125 men with mHSPC. Patients on this trial could have previously received ADT for up to 24 months in the adjuvant setting if the treatment had been completed at least 12 months prior to enrollment on the trial, or could have begun ADT up to 12 weeks before randomization, and could have received up to two cycles of docetaxel. Because the standard-of-care treatment for mHSPC changed just after this trial began (due to the CHAARTED trial), patients were given the option to initiate early treatment with docetaxel in addition to the treatment they were receiving on the trial.
Compared with a nonsteroidal anti-androgen, the addition of enzalutamide to ADT significantly reduced the risk of death by 33%, and reduced the time to PSA rise, clinical progression or death (whichever came first) by 61%. Enzalutamide prolonged survival in patients with both low and high volume metastatic disease. The addition of enzalutamide was deemed tolerable, however patients were more likely to experience fatigue, hypertension, falls, cardiac disorders and cognitive dysfunction than patients receiving a nonsteroidal anti-androgen. Enzalutamide patients also had about a 1% incidence of seizures. However, no survival benefit for enzalutamide over a nonsteroidal anti-androgen was seen in patients who additionally received docetaxel, and these patients experienced a modest increase in docetaxel-related side effects.
Dr. Michael Morris, the Prostate Cancer Section Head and Clinical Director of the GU Oncology Service at Memorial Sloan Kettering Cancer Center noted that “Following the results of TITAN and ENZAMET, men with metastatic disease who are either untreated or still responsive to testosterone-lowering agents have an unprecedented number of treatment options that improve their cancer outcomes. These results bring the number of such drugs to four – one chemotherapy, and three different therapies from two different classes of drugs that target the androgen receptor signaling pathway. Determining which drug is best for a given man will need additional research regarding the side effects of each drug, versus its benefits, a patient’s baseline health status, and his disease distribution and biology.”
PCF funded the original synthesis of both enzalutamide and apalutamide at UCLA, by Drs. Michael Jung, PhD and Charles Sawyers, MD. Early development of these drugs was also supported by funding from PCF.
Results from the TITAN and ENZAMET trials were also published in the prestigious medical journal, The New England Journal of Medicine.
The 2019 ASCO Annual Meeting was held in Chicago, IL, from May 31 to June 4, 2019