Two new advanced hormonal agents (apalutamide and enzalutamide) increase survival in metastatic hormone sensitive prostate cancer (mHSPC)

Erleada (apalutamide) has already been FDA-approved for use in non-metastatic castration-resistant prostate cancer (non-m CRPC), which affects relatively few men (remembering that metastatic was defined by bone scan/CT rather than PET scan). Now we have evidence that it increases overall survival in men with metastatic hormone-sensitive prostate cancer (mHSPC).

Chi et al. reported the early results of the TITAN randomized clinical trial at the ASCO meeting. The trial was conducted at 230 sites in the US and internationally. Patients received 240 mg/day of apalutamide (n=525) or placebo (n=527) plus ADT.

• It was double blinded.
• Prior treatments were allowed.
• 8% had prior treatment for localized PC
• 11% had prior docetaxel
• 63% had high-volume metastases
• 37% had low-volume metastases

After almost 2 years median follow-up, the outcomes were as follows:

• Apalutamide reduced mortality by 33%
• Apalutamide reduced radiographic progression or mortality by 52%
• Benefit was seen in all subgroups (i.e, volume of metastases and prior treatments)
• Time to docetaxel treatment was 61% longer in men getting apalutamide.
• Because of the success, men getting placebo were allowed to get apalutamide
• Grade 3 (serious) and grade 4 (life-threatening) toxicities were similar in both groups (41-42%)
• Discontinuations due to adverse events were low in both groups (8% for apalutamide, 5% for placebo)

(Update 9/18/19 It has been FDA approved for this indication).

Xtandi (enzalutamide) has been FDA-approved since 2012 for mCRPC after docetaxel and since 2014 for mCRPC before docetaxel. Sweeney et al.  reported the results of the ENZAMET randomized clinical trial at the ASCO meeting and in the NEJM. 1,125 patients at 82 sites in Australia, New Zealand, Ireland, Canada, and the UK received 160 mg/day of enzalutamide plus ADT or a first-generation anti-androgen (AA) (bicalutamide, nilutamide, or flutamide) plus ADT. It was unblinded and was reported earlier than expected.

• 3-year overall survival (3yrOS) was 79% for enzalutamide vs 72% for AA (Hazard Ratio = 0.66 - statistically significant)
• For men with high volume metastases, 3yrOS was 71% for enzalutamide vs 63% for AA (Hazard Ratio = 0.74 - not statistically significant)
• For men with low volume metastases, 3yrOS was 89% for enzalutamide vs 82% for AA (Hazard Ratio = 0.48 -  statistically significant)
• For men who also planned to receive early docetaxel, 3yrOS was 73% for enzalutamide vs 74% for AA (Hazard Ratio = 0.91 - not statistically significant)
• For men who did not plan to receive early docetaxel, 3yrOS was 83% for enzalutamide vs 70% for AA (Hazard Ratio = 0.51 - statistically significant)

Toxicity was higher for enzalutamide:

• Serious adverse events occurred in 42% of those taking enzalutamide vs 34% for AA
• Treatment discontinuation due to adverse events occurred in 33 patients taking enzalutamide vs 14 patients for AA
• Adverse events were higher in those who had taken docetaxel
• Fatigue was more common for men taking enzalutamide
• Seizures occurred in 7 patients taking enzalutamide and no patients for AA

(update 12/16/2019: It has been FDA approved for this indication)

Based on these successes, I'm sure the FDA will fast-track approval for both drugs for this new indication, joining Zytiga and Taxotere. Because they are already available for another indication, insurance may allow them off-label even sooner. The cost for either is about $12,000 for a 30-day supply. It is unknown if they are any more effective than abiraterone, which is now available as a new formulation called Yonsa for about $10,000 per month.